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Is the cytotoxic activity of phenanthriplatin dependent on the specific size of the phenanthridine ligand π system?
Abstract
The monofunctional Pt(II) drug phenanthriplatin is a leading preclinical anticancer drug, whose main characteristic is the presence of the extended aromatic system of the phenanthridine ligand, which allows intercalation. Intercalation, in turn, induces DNA unwinding and facilitates DNA binding. Aiming at verifying to what extent the peculiar cytotoxic activity of phenanthriplatin depends on the specific size of the aromatic system, two phenanthriplatin derivatives have been designed increasing the number of the rings in the N-heterocyclic ligand, and their reactivity has been computationally investigated. Both quantum mechanical DFT computations and molecular dynamics (MD) simulations have been employed to investigate some of the aspects that are considered important for the activity of Pt(II) monofunctional complexes. In particular, the substitution of the chlorido ligand with water, subsequent interaction of the aquated complexes with guanine as a model, eventual deactivation by the model N-acetyl methionine as well as intercalation into, binding to and distortion of DNA have been examined. The outcomes of such analysis have been compared with the analogous ones for the phenanthriplatin complex in order to highlight how the addition of one more ring to the phenanthridine ligand and, eventually, its identity influence the reactivity and, consequently, the cytotoxic profile of the complexes.
... In addition, such hindrance entails an opening of the intercalation site from one side, generating something like a pocket, instead of an enlargement of the entire site often observed for other intercalative agents. [21][22][23]82,83 However, as already drawn from the RMSD plot of the four residues defining each intercalation site, analyzing the whole trajectory, the opening of the various intercalation sites occurs during the intercalation process. Specifically, the intercalation causes an elongation of about 3 Å of the DNA double helix, in each investigated drug-DNA adduct. ...
A combined quantum-mechanical and classical molecular dynamics study of a recent Ru(II) complex with potential dual anticancer action is reported here. The main basis for the multiple action relies on the merocyanine ligand, whose electronic structure allows the drug to be able to absorb within the therapeutic window and in turn efficiently generate 1O2 for photodynamic therapy application and to intercalate within two nucleobases couples establishing reversible electrostatic interactions with DNA. TDDFT outcomes, which include the absorption spectrum, triplet states energy, and spin-orbit matrix elements, evidence that the photosensitizing activity is ensured by an MLCT state at around 660 nm, involving the merocyanine-based ligand, and by an efficient ISC from such state to triplet states with different characters. On the other hand, the MD exploration of all the possible intercalation sites within the dodecamer B-DNA evidences the ability of the complex to establish several electrostatic interactions with the nucleobases, thus potentially inducing DNA damage, though the simulation of the absorption spectra for models extracted by each MD trajectory shows that the photosensitizing properties of the complex remain unaltered. The computational results support that the anti-tumor effect may be related to multiple mechanisms of action.
... 2. Electrophylicity of the [ 3 FMN À 2 ]* state for two-electron transfer reactions (step 2 in Figure 2), thereby forming the ground state reduced [ 1 FMNH À 3 ] species. The mechanism by which this takes place in miniSOG is still unclear, and therefore, the double reduction is estimated considering: i) an outer sphere reaction, where the two electrons are transferred to the flavin, which is later protonated (reactions 1 and 2), ii) an inner sphere reaction, where the reduction occurs via the transfer of an hydride anion [33] to the ring (reaction 2). This has been assessed by calculating the electronic energy balances (ΔE) of the following reactions: ...
The unconventional bioorthogonal catalytic activation of anticancer metal complexes by flavin and flavoproteins photocatalysis has been reported recently. The reactivity is based on a two‐electron redox reaction of the photoactivated flavin. Furthermore, when it comes to flavoproteins, we recently reported that site mutagenesis can modulate and improve this catalytic activity in the mini Singlet Oxygen Generator protein (SOG). In this paper, we analyze the reductive half‐reaction in different miniSOG environments by means of density functional theory. We report that the redox properties of flavin and the resulting reactivity of miniSOG is modulated by specific mutations, which is in line with the experimental results in the literature. This modulation can be attributed to the fundamental physicochemical properties of the system, specifically (i) the competition of single and double reduction of the flavin and (ii) the probability of electron transfer from the protein to the flavin. These factors are ultimately linked to the stability of flavin‘s electron‐accepting orbitals in different coordination modes.
... On the other hand, within the great variety of nitrogenous heterocyclic systems of biological importance, the phenanthridine nucleus has aroused great interest in the scientific community and, particularly, in organic chemists and medicinal chemists due to the wide spectrum of activities they exhibit [23][24][25][26][27][28]. Many phenanthridine derivatives found in nature have turned out to be effective anticancer agents, which has motivated the design and implementation of the synthetic arsenal available to obtain them. ...
We hereby report an efficient method for the preparation of a series of new N-biphenyl-cinnamamides/3-arylpropanamides through a three–step, clean, good–yielding, environment–friendly microwave-assisted procedure for the Suzuki–Miyaura coupling/basic hydrolysis/N-amidation from 2-bromoacetanilides and arylboronic acids as available starting reagents. The N-biphenyl-3-arylpropanamides obtained were converted into new 6-phenethylphenanthridine derivatives carrying out a subsequent cyclization reaction by means of a Pictet–Hubert microwave–assisted process. The structures of the compounds were fully characterized by FT-IR, 1H, and 13C-NMR and are reported for the first time.
... 1 The significance of synthesis catalysed by biorelevant metals such as Mg, Ca, Mn, Fe, Cu, and Zn is again paramount for C-C and C-H activation processes, which are involved in the construction of pharmacologically important heterocycles such as quinolines, isoquinolines, acridines or phenanthridines, among others. 2,3 From the synthetic, biological, and pharmacological points of view, the phenanthridine core represents one of the most significant and appealing nitrogen-bearing heterocyclic systems that constitutes the general structure of numerous natural compounds, such as phenanthridine and benzo[c]phenanthridine-type alkaloids, trispheridine (A) or decarine (B), with notable antitumor and antiparasitic properties, 4,5 bioagents for molecular imaging techniques such as ethidium bromide (C) or propidium iodide (D), 6 anticancer drug candidates such as phenantriplatin (E) 7,8 and functional materials such as the axially chiral P,N-ligand PHENAP (F) 9 (Fig. 1). ...
An ecofriendly, efficient method of synthesis for new pharmacologically active 6-arylphenanthridines has been developed for the first time. The method involves consecutive microwave-assisted Suzuki-Miyaura and Pictet-Spengler processes starting from inexpensive...
... According to the softness S and hardness η indices, hard molecules are more stable than soft molecules because they have a wider energy gap. 61,62 Consequently, the soft compound was more active and elastic toward metal ions. As a result, the investigated L ligand is determined to be soft toward coordinating. ...
In this elucidation, the reactivity of isonicotinohydrazide derivative (3)(L) was reacted with the nitrate salts of Cr (III), Fe (III), Co (II), Ni (II), Cu (II) and Zn (II) to afford the corresponding stable metal coordination compounds. The synthesized metal coordination compounds were confirmed through physicochemical and analytical analysis such as elemental analysis, UV‐Visible, FT‐IR, TGA, Mass, 1H NMR, XRD, magnetic, and molar conductance analysis. All complexes exhibit distorted octahedral geometry except Zn (II) complex which has a distorted tetrahedral arrangement. Both the thermal stability and the kinetic parameter for all complexes were elucidated via TGA analysis and Coats‐Redfern method. XRD study suggested that the complexes have a partially amorphous structure which was further confirmed by calculating the crystallinity index. Moreover, the synthesized metal complexes exhibited excellent cytotoxicity activity contra lung cancer cells (A549) and liver cancer cells (HepG2) using neutral red uptake assay. The complexes of Fe (III), Ni (II) and Zn (II) showed higher cytotoxicity effect than doxorubicin against A549 and HepG2 cells for 24 h incubation. Furthermore, the Cr (III), Co (II), Zn (II) and Cu (II) coordination compounds showed more inhibitory influence when treated with A549 and HepG2 cells for 48 h incubation. The biological studies of these complexes were confirmed through molecular docking studies with different proteins such as (PDB ID: 2ITO) and (PDB ID: 5H38) and showed low binding energy and shortage bond length with different amino acids. Also, computational calculations of all metal complexes were carried out utilizing DFT/B3LYP/LANL2DZ basis set to detect the FMO, ESP, MEP and physical descriptor’s of them and confirms their reactivity.
... Hard molecules have higher stability due to a larger energy differential between the E LUMO and E HOMO than soft molecules according to the softness (S and ω) and the hardness (η) indices. [51,52] Therefore, the soft molecule is the more reactive one and a flexible donor toward the metal ions. Based on this, it is determined that the examined L 1 and L 2 ligands are soft toward coordinating. ...
In this investigation, we studied the mixing of two ligands, isonicotinohydrazide (L1) and 3‐hydroxyisonicotinic acid (L2) with different metal ions to afford the corresponding stable metal complexes. Consequently, intensive Physico‐chemical analysis including elemental analysis, UV‐Visible, FT‐IR, TGA, Mass, 1H NMR, XRD, magnetic, and molar conductance measurements has been performed. The thermal stability of all complexes was determined using TGA analysis, and the kinetic parameters were obtained using the Coats‐Redfern method. Both the degree of crystallinity and the unit cell of all complexes were determined utilizing XRD studies. Furthermore, these metal complexes exhibited excellent anti‐proliferative activity against human breast cancer (MCF‐7) and human liver cancer (HepG2) cell lines against the doxorubicin drug. The Co (II) complex outperformed all other metal complexes in terms of activity, which was confirmed by molecular docking stimulation via the binding energy with amino acids in a structural complex of KSHV thymidylate synthase (PDBID:5H38) and the Ternary Complex of KRIT1 bound to both the Rap1 GTPase and the Heart of Glass (HEG1) cytoplasmic tail (PDBID:4hdq) and shortage. Moreover, these metal complexes were optimized via theoretical investigation through a DFT/B3LYP/LANL2DZ basis set to confirm the stability of these metals theoretically and detect FMO orbitals, ESP, energy gap, and physical computational calculations. Eventually, the electrochemical features were explored using cyclic voltammetry (CV) and electrochemical impedance spectra (EIS).
... Due to its planar structure and aromaticity, intercalation of SAN, in its iminium cationic form, is very likely. Therefore, MD simulations were performed manually putting the molecule into the adopted B-DNA dodecamer model considering different positions across the major groove of the helix between two base pairs in analogy with our previous studies [60][61][62]. The examined DNA sites are shown in Figure 3A. ...
A computational investigation of the mechanism of dihydrosanguinarine (DHSAN) photoactivation and its conversion into the active drug sanguinarine (SAN) is here reported. The reaction mechanism of DHSAN photoconversion was fully explored by considering its excitation first, essential for generating one of the reactants, the 1O2, and then locating all the minima and transition states involved in the formation of SAN. Both forms of the drug present at physiological pH, namely, iminium cation and alkanolamine, were considered as products of such reaction. The ability of the generated drug SAN to induce cell apoptosis was then explored, taking into consideration two anticancer activities: the induction of DNA conformational and functional changes by intercalation and the absorption of light with proper wavelength to trigger type II photochemical reactions leading to 1O2 sensitization for photodynamic therapy application. Concerning the ability to work as photosensitizers, the outcomes of our calculations prove that DHSAN can easily be converted into the active SAN under visible and NIR irradiation through the application of two-photon excitation, and that the maximum absorption of SAN, once intercalated into DNA, shifts to the near region of the therapeutic window.
... The chosen intercalation sites, in which the drug was manually placed, were used in the study of photophysical properties. Several intercalation sites were considered as in our previous study, 57,58 and the selected ones are shown in Figure 3a and are named I, II, and III. In I, the drug is stacked within the thymine-adenine (TA) and cytosine-guanine (CG) base pairs. ...
Phenanthriplatin (PtPPH) is a monovalent platinum(II)-based complex with a large cytotoxicity against cancer cells. Although the aqua-activated drug has been assumed to be the precursor for DNA damage, it is still under debate whether the way in which that metallodrug attacks to DNA is dominated by a direct binding to a guanine base or rather by an intercalated intermediate product. Aiming to capture the mechanism of action of PtPPH, the present contribution used theoretical tools to systematically assess the sequence of all possible mechanisms on drug activation and reactivity, for example, hydrolysis, intercalation, and covalent damage to DNA. Ab initio quantum mechanical (QM) methods, hybrid QM/QM′ schemes, and independent gradient model approaches are implemented in an unbiased protocol. The performed simulations show that the cascade of reactions is articulated in three well-defined stages: (i) an early and fast intercalation of the complex between the DNA bases, (ii) a subsequent hydrolysis reaction that leads to the aqua-activated form, and (iii) a final formation of the covalent bond between PtPPH and DNA at a guanine site. The permanent damage to DNA is consequently driven by that latter bond to DNA but with a simultaneous π–π intercalation of the phenanthridine into nucleobases. The impact of the DNA sequence and the lateral backbone was also discussed to provide a more complete picture of the forces that anchor the drug into the double helix.
In the effort to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents, a large number of cisplatin variants continues today to be prepared and tested. One of the applied strategies is to use monofunctional platinum complexes that, unlike traditional bifunctional compounds, are able to form only a single covalent bond with nuclear DNA. Chirality, aquation reaction, interaction with guanine and N‐acetyl methionine as well as, intercalation into, binding to and distortion of DNA have been investigated by using both quantum mechanical DFT and molecular dynamics computations aiming at contributing to the elucidation of the molecular mechanism underlying the significantly enhanced spectrum of activity of the monofunctional PtII drug phenanthriplatin. Analogous calculations have been performed in parallel for other two less potent monofunctional PtII drugs, pyriplatin and enpyriplatin, which show very different cytotoxic effects.
We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ∼140 μs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/.
Significance
In this work we investigated the ability of phenanthriplatin, a novel, potent monofunctional platinum anticancer agent, to inhibit DNA replication. Biochemical assays using site-specifically platinated DNA probes revealed the ability of phenanthriplatin lesions to block DNA replication by all polymerases tested except for Pol η, which exhibited inefficient but high-fidelity lesion bypass. Crystallographic studies of Pol η stalled at different stages of translesion synthesis past phenanthriplatin-platinated DNA provided insight into the mechanism by which the lesion inhibits DNA polymerases to induce cellular toxicity. Cytotoxicity studies using cells derived from patients who do not express functional Pol η suggest that phenanthriplatin-based therapy will be useful to treat cancers resistant to cisplatin by upregulating Pol η expression.
DNA interstrand crosslinks (ICLs) formed by antitumor agents, such as cisplatin or mitomycin C, are highly cytotoxic DNA lesions.
Their repair is believed to be triggered primarily by the stalling of replication forks at ICLs in S-phase. There is, however,
increasing evidence that ICL repair can also occur independently of replication. Using a reporter assay, we describe a pathway
for the repair of cisplatin ICLs that depends on transcription-coupled nucleotide excision repair protein CSB, the general
nucleotide excision repair factors XPA, XPF and XPG, but not the global genome nucleotide excision repair factor XPC. In this
pathway, Rev1 and Polζ are involved in the error-free bypass of cisplatin ICLs. The requirement for CSB, Rev1 or Polζ is specific
for the repair of ICLs, as the repair of cisplatin intrastrand crosslinks does not require these genes under identical conditions.
We directly show that this pathway contributes to the removal of ICLs outside of S-phase. Finally, our studies reveal that
defects in replication- and transcription-dependent pathways are additive in terms of cellular sensitivity to treatment with
cisplatin or mitomycin C. We conclude that transcription- and replication-dependent pathways contribute to cellular survival
following treatment with crosslinking agents.
Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.
Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC(50) = 171-443 μmol/L), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 hours (IC(50) = 24 μmol/L). Pyriplatin caused a G(2)-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin-DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use.
DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.
The method of dispersion correction as an add-on to standard Kohn-Sham density functional theory (DFT-D) has been refined regarding higher accuracy, broader range of applicability, and less empiricism. The main new ingredients are atom-pairwise specific dispersion coefficients and cutoff radii that are both computed from first principles. The coefficients for new eighth-order dispersion terms are computed using established recursion relations. System (geometry) dependent information is used for the first time in a DFT-D type approach by employing the new concept of fractional coordination numbers (CN). They are used to interpolate between dispersion coefficients of atoms in different chemical environments. The method only requires adjustment of two global parameters for each density functional, is asymptotically exact for a gas of weakly interacting neutral atoms, and easily allows the computation of atomic forces. Three-body nonadditivity terms are considered. The method has been assessed on standard benchmark sets for inter- and intramolecular noncovalent interactions with a particular emphasis on a consistent description of light and heavy element systems. The mean absolute deviations for the S22 benchmark set of noncovalent interactions for 11 standard density functionals decrease by 15%-40% compared to the previous (already accurate) DFT-D version. Spectacular improvements are found for a tripeptide-folding model and all tested metallic systems. The rectification of the long-range behavior and the use of more accurate C(6) coefficients also lead to a much better description of large (infinite) systems as shown for graphene sheets and the adsorption of benzene on an Ag(111) surface. For graphene it is found that the inclusion of three-body terms substantially (by about 10%) weakens the interlayer binding. We propose the revised DFT-D method as a general tool for the computation of the dispersion energy in molecules and solids of any kind with DFT and related (low-cost) electronic structure methods for large systems.
CERTAIN platinum compounds completely but reversibly iiihibit cell division in Gram-negative rods1-4. These compounds have been tested for antitumour activity and we report some of the preliminary results. The platinum compounds inhibit sarcoma 180 and leukaemia L1210 in mice.
The crystal structure of the synthetic DNA dodecamer d(CpGpCpGpApApTpTpCpGpCpG) has been refined to a residual error of R = 17.8% at 1.9-A resolution (two-sigma data). The molecule forms slightly more than one complete turn of right-handed double-stranded B helix. The two ends of the helix overlap and interlock minor grooves with neighboring molecules up and down a 2(1) screw axis, producing a 19 degrees bend in helix axis over the 11-base-pair steps of the dodecamer. In the center of the molecule, where perturbation is least, the helix has a mean rotation of 36.9 degrees per step, or 9.8 base pairs per turn. The mean propeller twist (total dihedral angle between base planes) between A . T base pairs in the center of the molecule is 17.3 degrees, and that between C . G pairs on the two ends averages 11.5 degrees. Individual deoxyribose ring conformations as measured by the C5'-C4'-C3'-O3' torsion angle delta, exhibit an approximately Gaussian distribution centered around the C1'-exo position with delta avg = 123 degrees and a range of 79 degrees to 157 degrees. Purine sugars cluster at high delta values, and pyrimidine sugars cluster at lower delta. A tendency toward 2-fold symmetry in sugar conformation about the center of the molecule is detectable in spite of the destruction of ideal 2-fold symmetry by the molecular bending. More strikingly, sugar conformations of paired based appear to follow a "principle of anticorrelation," with delta values lying approximately the same distance to either side of the center value, delta = 123 degrees. This same anticorrelation is also observed in other DNA and DNA . RNA structures.
Most metastatic cancers are fatal. More than 80% of patients with metastatic testicular germ-cell tumours (TGCTs), however, can be cured using cisplatin-based combination chemotherapy. Why are TGCTs more sensitive to chemotherapeutics than most other tumour types? Answers to this question could lead to new treatments for metastatic cancers.
The effects produced in DNA by monofunctional or interstrand adducts of platinum(II) complexes have been summarized. The monofunctional adducts destabilize DNA in a sequence-dependent manner via conformational distortions, which may have a denaturational character. It has been suggested that this conformational alteration facilitates in DNA the formation of the bidentate DNA adducts, whose formation is associated with a permanent or transient local denaturation. In addition, DNA interstrand cross-linking by cis-diamminedichloroplatinum(II) and its trans isomer produce in DNA lesions that have quite different characteristics. It has been suggested that these differences may have relevance to the distinct antitumor efficacy of the two platinum isomers.
We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH3)2(py)Cl]⁺ or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH = trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH3)2(py)}²⁺ bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5′ side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)}²⁺. cDPCP–DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum–DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.
• cancer therapy
• nucleotide excision repair
• organic cation transporter
• RNA polymerase II inhibition
• x-ray crystal structure
Phenanthriplatin, a monofunctional anticancer agent derived from cisplatin, shows significantly enhanced DNA covalent binding activity compared to its parent complex. To understand the underlying molecular mechanism, we use single molecule studies with optical tweezers to probe the kinetics of DNA-phenanthriplatin binding as well as DNA binding to several control complexes. The time-dependent extension of single λ-DNA molecules were monitored at constant applied forces and compound concentrations, followed by rinsing with a compound-free solution. DNA-phenanthriplatin association consisted of fast and reversible DNA lengthening with time constant τ ~10 s, followed by slow and irreversible DNA elongation that reaches equilibrium in ~30 min. In contrast, only reversible fast DNA elongation occurs for its stereoisomer trans-phenanthriplatin, suggesting that the distinct two-rate kinetics of phenanthriplatin is sensitive to the geometric conformation of the complex. Furthermore, no DNA unwinding is observed for pyriplatin, in which the phenanthridine ligand of phenanthriplatin is replaced by the smaller pyridine molecule, indicating that the size of the aromatic group is responsible for the rapid DNA elongation. These findings suggest that the mechanism of binding of phenanthriplatin to DNA involves rapid, partial intercalation of the phenanthridine ring followed by slower substitution of the adjacent chloride ligand by, most likely, the N7 atom of a purine base. The cis isomer affords the proper stereochemistry at the metal center to facilitate essentially irreversible DNA covalent binding, a geometric advantage not afforded by trans phenanthriplatin. This study demonstrates that reversible DNA intercalation can be employed to provide a robust transition state that is efficiently converted to an irreversible DNA-Pt bound state.
The monofunctional platinum drug phenanthriplatin (phenPt) blocks the replication of cancer cells even if it reacts with only one guanine base. However, there is still insufficient experimental data to improve its cytotoxicity and all previously proposed chemical modifications of the parent structure have resulted in a loss of activity. We use theoretical tools to illustrate the key steps in the biological mechanisms of phenPt—that is, its activation in water and the subsequent attack on DNA. Our simulations suggest that the measured kinetic parameters, which are based on free nucleobases in solution, need to be reinterpreted because the self-assembled stacked reactive adduct formed in the reaction is inaccessible in real DNA. The constants reported here will help guide future work in the synthesis of anticancer platinum drugs.
The continued use of platinum-based chemotherapeutic drugs in the clinic mandates the need for further investigation of the biological activity of structural analogues of the clinically approved complexes. Of interest are monofunctional platinum(II) complexes, which bear only one labile ligand, for which it is believed that each complex binds to DNA only once. Pyriplatin ([PtCl(NH3)2(py)]⁺) and enpyriplatin ([PtCl(en)(py)]⁺) are both monofunctional platinum(II) complexes that bear a pyridine ligand and a labile chlorido ligand, differing in their cis‑ammine and ethane-1,2-diamine (en) ligands respectively. Despite their similar structure, the complexes exhibit dramatically different cytotoxicities. In this study, we synthesized and characterized both complexes in terms of their cytotoxicity, lipophilicity, DNA binding and cellular accumulation. There was no significant difference between the lipophilicities of the complexes and both complexes exhibited monofunctional type binding, but it was the temporal accumulation profiles of the two complexes which differed greatly. The complexes were further analyzed with size exclusion chromatography coupled with inductively coupled plasma mass spectrometry (SEC-ICP-MS) to determine the platination state of the proteins. Consistent with the accumulation studies, pyriplatin bound to proteins in far greater amounts than enpyriplatin, and this study also revealed some different protein targets between the bifunctional cisplatin and monofunctional pyriplatin. This study highlights the need for more sophisticated techniques, such as SEC-ICP-MS, to determine not only how much of a platinum complex accumulates in cells, but also the speciation and metabolites of platinum anticancer drugs.
Pulse radiolysis measurements of the decay of hydrated electrons in solutions containing different concentrations of the oligonucleotide GTG with and without a cisplatin adduct show that the presence of a cisplatin moiety accelerates the reaction between hydrated electrons and the oligonucleotide. The rate constant of the reaction is found to be 2.23×10(10) mol(-1) L s(-1), which indicates that it is diffusion controlled. In addition, we show for the first time the formation of a Pt(I) intermediate as a result of the reaction of hydrated electrons with GTG-cisplatin. A putative reaction mechanism is proposed, which may form the basis of the radiosensitization of cancer cells in concomitant chemo-radiation therapy with cisplatin.
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is given to its molecular mechanisms of action, and its undesirable side effects.
MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson–Boltzmann Model, the Generalized Born Model, and the Reference Interaction Site Model. Vibrational frequencies may be calculated using normal mode or quasi-harmonic analysis to approximate the solute entropy. Specific interactions can also be dissected using free energy decomposition or alanine scanning. A parallel implementation significantly speeds up the calculation by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calculations. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
The monofunctional platinum complex cis-[Pt(NH3)2Cl(Am)]+, also known as phenanthriplatin, where Am is the N-heterocyclic base phenanthridine, has promising anticancer activity. Unlike bifunctional compounds such as cisplatin, phenanthriplatin can form only one covalent bond to DNA. Another distinguishing feature is that phenanthriplatin is chiral. Rotation about the Pt-N bond of the phenanthridine ligand racemizes the complex, and the question arises as to whether this process is sufficiently slow under physiological conditions to impact its DNA-binding properties. Here we present the results of NMR spectroscopic, X-ray crystallographic, molecular dynamics, and density functional theoretical investigations of diastereomeric phenanthriplatin analogs in order to probe the internal dynamics of phenanthriplatin. These results reveal that phenanthriplatin rapidly racemizes under physiological conditions. The information also facilitated the interpretation of the NMR spectra of small molecule models of phenanthriplatin-platinated DNA. These studies indicate, inter alia, that one diastereomeric form of the complexes cis-[Pt(NH3)2(Am)(R-Gua)]2+, where R-Gua is 9-methyl- or 9-ethylguaine, is preferred over the other, the origin of which stems from an intramolecular interaction between the carbonyl oxygen of the platinated guanine base and a cis-coordinated ammine. The relevance of this finding to the DNA-damaging properties of phenanthriplatin and its biological activity is discussed.
Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms monofunctional DNA lesions having a structure and spectrum of anticancer activity distinct from those of cisplatin. Understanding the functional interplay between phenanthriplatin-modified DNA and the RNA polymerase II (Pol II) transcription machinery is an important step toward elucidating the mechanism of action of phenanthriplatin. In this study, we present the first systematic mechanistic investigation that addresses how a site-specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Strikingly, we find that Pol II processing of the phenanthriplatin lesion is significantly different from that of the canonical cisplatin DNA 1,2-d(GpG) intrastrand cross-link. Our study reveals that a majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner and that the specificity for CTP incorporation is essentially the same as for undamaged dG on the template. In addition, we observe that a small portion of Pol II undergoes a slow, error-prone bypass of the phenanthriplatin-dG lesion. Moreover, Pol II transcription switches from an effective "error-free" to a slow "error prone" mode during lesion bypass, resembling DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error-prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis.
Summary Nonrelativistic and quasirelativisticab initio pseudopotentials substituting the M(Z-28)+-core orbitals of the second row transition elements and the M(Z-60)+-core orbitals of the third row transition elements, respectively, and optimized (8s7p6d)/[6s5p3d]-GTO valence basis sets for use in molecular calculations have been generated. Additionally, corresponding spin-orbit operators have also been derived. Atomic excitation and ionization energies from numerical HF as well as from SCF pseudopotential calculations using the derived basis sets differ in most cases by less than 0.1 eV from corresponding numerical all-electron results. Spin-orbit splittings for lowlying states are in reasonable agreement with corresponding all-electron Dirac-Fock (DF) results.
Platinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. These efforts continue today with increased realization that new strategies are needed to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents. One approach has been the use of so-called "non-traditional" platinum(II) and platinum(IV) compounds that violate the structure-activity relationships that governed platinum drug-development research for many years. Another is the use of specialized drug-delivery strategies. Here we describe recent developments from our laboratory involving monofunctional platinum(II) complexes together with a historical account of the manner by which we came to investigate these compounds and their relationship to previously studied molecules. We also discuss work carried out using platinum(IV) prodrugs and the development of nanoconstructs designed to deliver them in vivo.
The ability of simple potential functions to reproduce accurately the density of liquid water from −37 to 100 °C at 1 to 10 000 atm has been further explored. The result is the five-site TIP5P model, which yields significantly improved results; the average error in the density over the 100° temperature range from −37.5 to 62.5 °C at 1 atm is only 0.006 g cm−3. Classical Monte Carlo statistical mechanics calculations have been performed to optimize the parameters, especially the position of the negative charges along the lone-pair directions. Initial calculations with 216 molecules in the NPT ensemble at 1 atm focused on finding a model that reproduced the shape of the liquid density curve as a function of temperature. Calculations performed for 512 molecules with the final TIP5P model demonstrate that the density maximum near 4 °C at 1 atm is reproduced, while high-quality structural and thermodynamic results are maintained. Attainment of high precision for the low-temperature runs required sampling for more than 1 billion Monte Carlo configurations. In addition, the dielectric constant was computed from the response to an applied electric field; the result is 81.5±1.5 at 25 °C and the experimental curve is mirrored from 0–100 °C at 1 atm. The TIP5P model is also found to perform well as a function of pressure; the density of liquid water at 25 °C is reproduced with an average error of ∼2% over the range from 1 to 10 000 atm, and the shift of the temperature of maximum density to lower temperature with increasing pressure is also obtained. © 2000 American Institute of Physics.
The diffusion constant of TIP5P [J. Chem. Phys. 112, 8910 (2000)], the recently developed five-site rigid nonpolarizable model of liquid water that significantly improves the description of water’s density anomaly, has been calculated at a range of temperatures between −25 °C and 75 °C and pressures between 1 atm and 3000 atm. The diffusion constant, in units of 10−5 cm2/s, for TIP5P water at 25 °C and 1 atm is 2.62±0.04 as compared with the experimental value of 2.30. This is a significant improvement over most commonly used water models, e.g., for TIP4P and TIP3P [J. Chem. Phys. 79, 926 (1983)] the diffusion constants are 3.29±0.05 and 5.06±0.09, respectively, and for SPC it is 3.85±0.09. The diffusion constant of TIP5P decreases dramatically with decreasing temperature, as is observed experimentally, and the change in the diffusion constant as pressure is increased is also consistent with experimental results. © 2001 American Institute of Physics.
A wide variety of Platinum(II) complexes have been investigated for antitumor activity against Sarcoma 180 in Swiss white female mice. In general, only neutral complexes exhibit activity while charged species are inactive and relatively nontoxic. A series of complexes of the type cis-[PtA2X2] (where A2 is either two monodentate or one bidentate amine ligand and X2 is either two monodentate or one bidentate anionic ligand) have been studied with A and X being systematically varied. This has resulted in the identification of at least ten potentially active antitumor drugs. Trans isomers are inactive in comparison with active cis complexes and the presence of cis-reactive ligands appears to be a necessary parameter for antitumor activity. Complexes with highly reactive ligands such as cis-[Pt(NH3)2(H3O)2] (NO3)2 are highly toxic. Palladium(II) complexes, which are analogs of the active Platinum(II) compounds, have been found to be inactive.
Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatin-based chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologic-based mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.
Monofunctional platinum(II) complexes of general formula cis-[Pt(NH(3))(2)(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH(3))(2)(phenanthridine)Cl]NO(3), which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5'-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links.
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
Platinum-containing drugs are widely used to treat cancer in a variety of clinical settings. Their mode of action involves the formation of DNA adducts, which facilitate apoptosis in cancer cells. Cisplatin binds to the N7 position of the purine DNA bases forming intrastrand cross-links between either two adjacent guanines [cis-Pt(NH(3))(2)d(pGpG), 1,2-GG] or an adjacent adenine and guanine [cis-Pt(NH(3))(2)d(pApG), 1,2-AG)]. The cytotoxic efficacy for each of the different types of DNA adducts and the relationship between adduct levels in tumor cells and blood are not well understood. By using these Pt-containing adduct species as biomarkers, information on a patient's response to chemotherapy would be directly related to the mode of action of the drug. This type of analysis requires the most sensitive and specific methods available, to facilitate detection limits sufficient to measure the DNA adduct in the limited sample quantities available from patients. This was achieved in the current study by coupling a highly specific enzyme-based adduct isolation method with a sensitive detection system based on HPLC coupled to inductively coupled plasma mass spectrometry to measure the 1,2-GG cisplatin adducts formed in DNA. The method was developed and validated using calf thymus DNA and two different adenocarcinoma cell lines. The values for the limit of detection (LOD) and the limit of quantitation determined for the 1,2-GG cisplatin adduct were 0.21 and 0.67 fmol per microg DNA, respectively. This corresponds to an absolute LOD of 0.8 pg as Pt for the 1,2-GG adduct. Cisplatin-sensitive (H23) and -resistant (A549) tumor cells were exposed to the drug, and the 1,2-GG adduct levels were measured over a 24 h time period. The results showed a statistically significant (P < 0.05) higher concentration in the sensitive cells as compared to the resistant cells after repair for 7 h. Although the adduct concentration present fell at subsequent time points (12 and 24 h), the levels in each cell line were broadly similar. The protocol was then applied to the analysis of patient samples taken before and then 1 h after treatment. The 1,2-GG cisplatin adduct was present in the range from 113 to 1245 fg Pt per microg DNA in all of the patient samples taken after treatment. Although the adduct was not present at levels greater than the LOD in the initial pretreatment samples, trace amounts were discernible in some patient samples on their third treatment cycle.
The effects on thermal stability and conformation of DNA produced by the monofunctional adducts of chlorodiethylenetriamineplatinum(II) chloride ([Pt(dien)Cl]Cl) have been investigated. Oligodeoxyribonucleotide duplexes of varying lengths (9-20 base pairs) and of varying central trinucleotide sequences were prepared and characterized that contained site-specific and unique N(7)-guanine adducts. Included are adducts at the sequences of d(AGC), d(AGT), d(CGA), d(TGA), d(TGC), and d(TGT). All these monofunctional adducts decrease the melting temperature (Tm) of the duplexes. This destabilization effect exhibits a sequence-dependent variability. The highest lowering of Tm is observed for the modified duplexes containing the central sequence of pyrimidine-guanine-pyrimidine. The destabilization effect is reduced with decreasing concentrations of Na+. Polarography, circular dichroism, phenanthroline-copper, and chemical probes reveal conformational distortions spreading over several base pairs around the adduct. The effects of monofunctional platinum(II) adducts on conformational distortions in DNA exhibit a sequence-dependent variability similar to those on thermal stability of DNA. The influence of the monofunctional adduct formed by cis-diamminemonoaquamonochloroplatinum(II) on the stability of the oligonucleotide duplex has been also studied. This lesion decreases thermal stability of DNA in the same way as does the adduct of [Pt(dien)Cl]Cl.
A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.
Inhibition of DNA replication by the antitumor drug cis-diamminedichloroplatinum (II) (cis-DDP) has been proposed to be responsible for its cytotoxicity. Treatment of primed phage M13 mp8 viral DNA templates with the drug followed by second-strand synthesis using large fragment DNA polymerase I reveals that cis-DDP forms an adduct with DNA that inhibits DNA synthesis in vitro. This inhibition occurs at all (dG)n (n greater than or equal to 2) sequences in the template strand, confirming that these regions are the major cis-DDP binding sites on DNA. trans-Diamminedichloroplatinum (II), which is inactive as a drug, also forms adducts that inhibit DNA synthesis. Although considerably lower specificity is observed with the trans isomer, there appears to be a preference for d(GpNpG) sequences, where N is any intervening nucleotide. The monofunctional adduct formed between chlorodiethylenetriamineplatinum(II) chloride and DNA does not inhibit DNA synthesis in this system.
VMD is a molecular graphics program designed for the display and analysis of molecular assemblies, in particular biopolymers such as proteins and nucleic acids. VMD can simultaneously display any number of structures using a wide variety of rendering styles and coloring methods. Molecules are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resolution raster images of displayed molecules may be produced by generating input scripts for use by a number of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate molecular dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biology, which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs. VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
IN an investigation of the possible effects of an electric field on growth processes in bacteria, we have discovered a new and interesting effect. In E. coli, the presence of certain group VIIIb transition metal compounds in concentrations of about 1-10 parts per million of the metal in the culture medium causes an inhibition of the cell division process. The bacteria form long filaments, up to 300 times the normal length, which implies that the growth process is not markedly affected.
We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.
Effects of adducts of [PtCl(NH3)3]Cl or chlorodiethylenetriamineplatinum(II) on DNA stability were studied with emphasis on thermodynamic origins of that stability. Oligodeoxyribonucleotide duplexes (15-bp) containing the single, site-specific monofunctional adduct at G-residues of the central sequences TGT/ACA or 5'-AGT/5'-ACT were prepared and analyzed by differential scanning calorimetry, temperature-dependent ultraviolet absorption and circular dichroism. The unfolding of the platinated duplexes was accompanied by relatively small unfavorable free energy terms. This destabilization was enthalpic in origin. On the other hand, a relatively large reduction of melting temperature (T(m)) was observed as a consequence of the monofunctional adduct in the TGT sequence, whereas T(m) due to the adduct in the AGT sequence was reduced only slightly. We also examined the efficiency of the mammalian nucleotide excision repair system to remove from DNA the monofunctional adducts and found that these lesions were not recognized by this repair system. Thus, rather thermodynamic than thermal characterization of DNA adducts of monofunctional platinum compounds is a property implicated in the modulation of downstream effects such as protein recognition and repair.
Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are widely used in cancer chemotherapy. Platinum-DNA adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. This review focuses on recently discovered cellular pathways that are activated in response to cisplatin, including those involved in regulating drug uptake, the signalling of DNA damage, cell-cycle checkpoints and arrest, DNA repair and cell death. Such knowledge of the cellular processing of cisplatin adducts with DNA provides valuable clues for the rational design of more efficient platinum-based drugs as well as the development of new therapeutic strategies.
The importance of platinum drugs in cancer chemotherapy is underscored by the clinical success of cisplatin [cis-diamminedichloroplatinum(II)] and its analogues and by clinical trials of other, less toxic platinum complexes that are active against resistant tumors. The antitumor effect of platinum complexes is believed to result from their ability to form various types of adducts with DNA. Nevertheless, drug resistance can occur by several ways: increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. This review focuses on mechanisms of resistance and sensitivity of tumors to conventional cisplatin associated with DNA modifications. We also discuss molecular mechanisms underlying resistance and sensitivity of tumors to the new platinum compounds synthesized with the goal to overcome resistance of tumors to established platinum drugs. Importantly, a number of new platinum compounds were designed to test the hypothesis that there is a correlation between the extent of resistance of tumors to these agents and their ability to induce a certain kind of damage or conformational change in DNA. Hence, information on DNA-binding modes, as well as recognition and repair of DNA damage is discussed, since this information may be exploited for improved structure-activity relationships.
In molecular mechanics (MM) studies, atom types and/or bond types of molecules are needed to determine prior to energy calculations. We present here an automatic algorithm of perceiving atom types that are defined in a description table, and an automatic algorithm of assigning bond types just based on atomic connectivity. The algorithms have been implemented in a new module of the AMBER packages. This auxiliary module, antechamber (roughly meaning "before AMBER"), can be applied to generate necessary inputs of leap-the AMBER program to generate topologies for minimization, molecular dynamics, etc., for most organic molecules. The algorithms behind the manipulations may be useful for other molecular mechanical packages as well as applications that need to designate atom types and bond types.
The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful anticancer drugs. Although carboplatin--a second-generation analogue that is safer but shows a similar spectrum of activity to cisplatin--was introduced in the 1980s, the pace of further improvements slowed for many years. However, in the past several years interest in platinum drugs has increased. Key developments include the elucidation of mechanisms of tumour resistance to these drugs, the introduction of new platinum-based agents (oxaliplatin, satraplatin and picoplatin), and clinical combination studies using platinum drugs with resistance modulators or new molecularly targeted drugs.
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