PreprintPDF Available

Molecular Modeling Study of New Platinum(VI)Complexes as Anticancer Chemotherapy

Authors:
Preprints and early-stage research may not have been peer reviewed yet.
A preview of the PDF is not available
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
The representation of solution, problem and implementation spaces with interrelated attributes which will help to the chemical and related scientific research and software development community. Scientific computing will help to address some of the challenges in computational chemistry and process systems particularly computational tasks that scale exponentially with various computational problems from chemistry domain. To design Knowledge Management (KM) base therefore has a lot to offer to a chemistry lab. Our main purpose is to identify computational problems of high priority to progress in chemical knowledge management initiatives that should be undertaken with support provided in the development of open source ICT tools for the computational chemistry domain. This paper presents algorithms, software development and computational complexity analysis for problems arising in the Computational Chemistry domain. I. COMPUTATIONAL CHEMISTRY COMPUTATIONS Use of methodical approximation and computer programs to obtain results relative to chemical problems. Computational chemistry is simply the application of chemical, mathematical and computing skills to the solution of interesting chemical problems. It uses computers to produce information such as properties of molecules and/or simulated experimental results. Some common computer software used for computational chemistry includes,Nlopt , MATLAB, TINKER , Gaussian etc.(8). Also computational chemistry is based on an approximations and assumptions. Computational Chemistry Calculate Energy, Structure, and Properties. Computations of this type are derived directly from theoretical principles, with no inclusion of experimental data. Mathematical approximations are usually a simple functional form for an approximate solution to a differential equation. A mathematical method that is sufficiently well developed that it can be automated for implementation on a computer. The input data for these computational problems are laboratory experiments, where some lead compounds were identified. The problem is to generate new laboratory experiments that will accelerate the likelihood of discovering new, more powerful compounds/substances. In order to do so we have to solve inverse problems based on specific indices. One wants several solutions for the inverse problem that are as diverse (i.e. different chemical structure) as possible. Based on them, a new combinatorial library is created, and new lead compounds are discovered. (1). II. CHALLENGES IN COMPUTATIONAL CHEMISTRY DOMAIN  Invent new computer tools and logistics methods to reduce significantly the time needed for commercializing new drugs.  Invent new algorithms to globally optimize at the worldwide level the use of raw materials, energy, and environmental impact of chemical processes.
Article
Full-text available
Lipophilicity is a crucial parameter for drug discovery, usually determined by the logarithmic partition coefficient (Log P) between octanol and water. However, the available detection methods have restricted the widespread use of the partition coefficient in inorganic medicinal chemistry, and recent investigations have shifted towards chromatographic lipophilicity parameters, frequently without a conversion to derive Log P. As high-performance liquid chromatography (HPLC) instruments are readily available to research groups, a HPLC-based method is presented and validated to derive the partition coefficient of a set of 19 structurally diverse and cytotoxic platinum(IV) complexes exhibiting a dynamic range of at least four orders of magnitude. The chromatographic lipophilicity parameters φ0 and Log kw were experimentally determined for the same set of compounds, and a correlation was obtained that allows interconversion between the two lipophilicity scales, which was applied to an additional set of 34 platinum(IV) drug candidates. Thereby, a φ0 = 58 corresponds to Log P = 0. The same approaches were successfully evaluated to determine the distribution coefficient (Log D) of five ionisable platinum(IV) compounds to sample pH-dependent effects on the lipophilicity. This study provides straight-forward HPLC-based methods to determine the lipophilicity of cytotoxic platinum(IV) complexes in the form of Log P and φ0 that can be interconverted and easily expanded to other metal-based compound classes.
Article
Full-text available
In this study, the contribution of the bond C-I has been derived and incorporated in empirical formula to calculate zero-point energies (ZPE) of Iodo compounds. The calculated ZPE for 38 molecules containing this bond correlate well with experimental values. The comparison of these results with semiempirical (AM 1) ZPE appears very satisfactory .
Article
Full-text available
The photocatalyzed insertion of dioxygen into the Pt(II)-methyl bond in terpyridine platinum complexes has been shown to proceed efficiently, but its mechanism remains a challenge. In particular, there are serious counter-intuitive differences in the reactivity of structurally similar complexes. M06 calculations in solvent with a valence double-zeta basis set supplemented by polarization and diffusion shells (benchmarked against omegaB97x-D calculations with a larger basis set) are able to provide a satisfactory mechanistic answer. The proposed mechanism starts with absorption of a photon by the metal complex, which then evolves to a triplet state that reacts with the triplet dioxygen fragment. A variety of possible reaction paths have been identified, some leading to the methylperoxo product, others reverting to reactants; and the validity of some of these paths has been confirmed by additional experiments. The balance between the barriers towards productive and unproductive paths reproduces the diverging experimental behavior of similar complexes and provides a general mechanistic picture for these processes.
Article
Full-text available
Eight pairs of cis–trans isomeric homoleptic platinum(II) complexes based on N-alkyl- or aryl-substituted 2,2′-biimidazole ligands were synthesized, and their photophysical properties were investigated. The cis and trans isomers readily interconvert at slightly elevated temperature, implying that the activation barrier for this process is low. Single crystal X-ray diffraction analysis revealed that the complexes have an ideal square-planar geometry. Their UV–Vis spectra showed lower energy absorption bands in the range of 345–378 nm, which are assigned to the typical MLCT mixed with LC transitions. In frozen glass solution at 77 K and also in the powder state, these complexes exhibit green emission ranging from 440 to 540 nm with photoluminescence quantum yields of 3.3–24.4%. The emitting excited state is dominated by ³ππ* character with some contributions from ³MLCT according to the excitation spectra.
Article
Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC50 values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin.