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Some naturally occurring macrocycles displaying a variety of medicinally important biological activities.
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Macrocyclic natural products often display remarkable biological activities, and many of these compounds (or their derivatives) are used as drugs. The chemical diversity of these compounds is immense and may provide inspiration for innovative drug design. Therefore, a database of naturally occurring macrocycles was analyzed for ring size, molecular...
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... decided to have a closer look into the principles of macrocyclic natural products, structurally and conceptually, based on some basic chem- informatic and metabolic observations. Naturally occurring macrocycles often have very complex structures and remark- ably high activities (Figure 1). The variety in ring sizes and chemical constitution is overwhelming. ...
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... relatively high occurrence of macrocycles in nature may be rationalized by the fact that they constitute an equilibrium or compromise between conformational preorganization (i.e. less entropy loss upon docking) and flexibility to achieve optimal binding properties to their biological target, which also explains their often unrivaled activities. The variety in structure and bio- logical activity of naturally occurring macrocycles is demon- strated by comparing FK-506 (1, immunosuppressant), ery- thromycin A (2) and vancomycin (3, antibiotic), epothilone B (4, anticancer), amphotericin B (5, antifungal), and K-13 (6, ACE inhibitor) (Figure 1). ...
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... the variety in structures is large, the variability in substructures is essentially limited to the available biosyn- thetic pathways. The complexity arises from the versatility of the separate metabolic pathways and the possibility to com- bine them ( Figure 10) [3,4]. The basis of these metabolic pathways is formed by simple, repetitive processes, mostly iterative in nature. ...
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... heterocycle(s), mostly 5-or 6-membered rings, can be endocyclic or exocyclic. Some examples are given in Figure 1 (1, 3-6), and here with compounds 9-12. heterocycle formation, eliminations, and/or side chain attach- ment reactions. ...
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... formation, eliminations, and/or side chain attach- ment reactions. The course of steps III and IV in Figure 10 may be inverted or repeated. ...
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... macrolide antibiotic erythromycin (Figure 11) provides a good example for diversity enhancement by macrocyclization, polyketide and sugar metabolism, and post-modification. In its biosynthesis, a linear polyketide is cyclized to form a macrocyclic aglycon precursor, which is subsequently modified by two oxidation reactions. ...
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... more precisely, how is such a complex product synthesized alongside primary metabolism? Figure 11. Complexity enhancement in erythromycin biosynthesis after the linear polyketide formation. ...
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... specific PKS, 6-deoxyerythronolide B synthase (DEBS) consists of three polypeptide chains (DEBS 1, 2, and 3). Each chain com- prises two modules, and each module consists of several do- mains (see Figure 12). Each module adds an acyl residue to the growing polyketide chain by the combined action of its domains. ...
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... ketosynthase (KS) domain then transfers the ACP-bound acyl residue to the next module in a Claisen-type reaction. Of- ten, the resulting ketone is reduced by a ketoreductase (KR) Figure 12. Schematic representation of 6-deoxyerythronolide B synthase (DEBS). ...
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... con- trast to polyketides and cyclopeptides, the stereocenters in terpenoids are introduced by selective cyclization and post- modification reactions. The divergent synthetic routes of ter- penoid biosynthesis are a consequence of the evolution of di- versity in terpene cyclases [62,63] such that different active Figure 13. Biosynthetic pathways to casbene and taxadiene. ...
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... the vast majority of isoprenoids is produced by eukaryotes, there have been few reports of eubacterial isoprenoid cyclases and their genes, such as squalene-hopene cyclases [73]. Almost all of the naturally occurring terpenoid macrocycles or derivatives fit into the geranylgeranyl diphosphate (GGPP) derived diter- pene family with C 20 (Figure 13), supporting our preliminary idea that the high numbers of 13-and 14-membered, as well as some 15-and 16-membered, all-carbon macrocycles could be derived from this precursor rather than a polyketide one. ...
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... [82,83] and taxadiene [84,85] synthases are rep- resentative of the second class of diterpene cyclases. Casbene Figure 14. Structures of some macrocyclic diterpenoids and subsequent transannular cyclization products [86][87][88]. ...
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... is a macrocyclic diterpene phytoalexin with antibacterial and antifungal activity [64,65], whereas taxadiene (15) repre- sents the diterpenoid portion of the important anticancer agent Taxol R (Paclitaxel) [31,[42][43][44]. Both compounds are formed from geranylgeranyl diphosphate by the action of their cor- responding cyclases through ionization of the diphosphate group to an allylic carbocation [69] followed by cyclization and deprotonation to the olefins ( Figure 13). The formation of the macrocyclic casbene involves the simultaneous formation of a cyclopropane ring [27]. ...
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... huge amount of bioactive macrocyclic diterpenoids, which have been reported in the recent years [71,[86][87][88] (see Figures 13 and 14), as well as the high number of 14-membered macrocycles, suggest that this biosynthetic mechanism is widespread in a large variety of organisms, and this dominance is reflected in our statistical results. Exami- nation of their striking structures confirms that most of them possess a casbene-type skeleton and therefore their chemical diversity is primarily due to post-cyclization modifications, which include transannular cyclization, lactonization, oxida- tion and epoxidation, alkyl migration, and acylation steps. ...
Citations
... [1] This broad definition encompasses a large diversity of synthetic or naturally occurring compounds. Indeed, many macrocycles are found in nature thanks to the diversity of biosynthetic routes, [2] but the interest in synthetic macrocycles stems from the appearance of Host-Guest chemistry described by Cram, [3] as calixarenes were developed. Cram followed Pedersen's and Lehn's leads, who developed namely crownethers and cryptands. ...
Thanks to supramolecular interactions of macrocyclic compounds with their guest ions or molecules, macrocycles have found wide applications in molecular and chiral recognition, separation, transportation, molecular machines, and so on. Photoswitchable macrocycles are especially appealing and attracting more and more interest because the embedded molecular photoswitch enables dynamic control of molecular shape, conformation, and different properties by light, a non‐invasive, remote and highly tunable stimulus. With available photochromic compounds, various photoswitchable macrocycles have been developed. In this review paper, we describe the recently reported photoswitchable macrocyclic compounds, with a focus on the control of the macrocyclic structure, dynamic, photo or thermal isomerization, as well as their applications on encapsulation and release of ionic or aromatic species, on the reversible modulation of chemical, biological, electronic, fluorescent and chiroptical properties by light.
... Macrocyclic compounds are a hot topic in many fields of chemistry and related sciences [1][2][3][4]. In particular, macrocycles are promising ligands for applied radiochemistry and radiopharmacy [5,6]. ...
A reaction of acyl chlorides derived from 1,10-phenanthroline-2,9-dicarboxylic acids with piperazine allows the preparation of the corresponding 24-membered macrocycles in good yield. The structural and spectral properties of these new macrocyclic ligands were thoroughly investigated, revealing promising coordination properties towards f-elements (Am, Eu). It was shown that the prepared ligands can be used for selective extraction of Am(III) from alkaline-carbonate media in presence of Eu(III) with an SFAm/Eu up to 40. Their extraction efficiency is higher than calixarene-type extraction of the Am(III) and Eu(III) pair. Composition of macrocycle-metal complex with Eu(III) was investigated by luminescence and UV-vis spectroscopy. The possibility of such ligands to form complexes of L:Eu = 1:2 stoichiometry is revealed.
... Macrocycles can be found in bio active natural products such as erythromycin, rapamycin, vancomycin, cyclosporin, epothilone, and synthetic active molecules, [1][2][3][4][5][6][7]. Macrocyclic compounds have unique structural feature. ...
Two new series of linear and angular furan pyrazole-4-carboxaldehydes (3a-c; 4a-c), and furopyrazole-annulated macrocycles (7a-d; 8a-d) have been synthesized. The pyrazole-4-carboxaldehydes were synthesized by Vilsmeier-Haack reaction. The reduction of the linear and angular phenyl pyrazole aldehydes yielded the corresponding alcohols. These precursors upon alkylation with dibromoalkanes gave the new serious of fused linear and angular target library. All the synthesized compounds were characterized by IR, 1 H, 13 C NMR, and LCMS spectral data and elemental analyses. All the synthesized pyrazole-4-carboxaldehydes and macrocyclic compounds were screened for their antimicrobial activity.
... Cyclopeptide alkaloids (CPAs) are macrocyclic compounds (13-15 members), defined as heterocyclopeptides due to the presence of a styrylaminine moiety. 1 They are commonly found in the Rhamnaceae family, especially in Ziziphus species, but are also present in other families like Asteraceae, Celastraceae, Euphorbiaceae, and Rubiaceae. According to their ring characteristics, CPAs are divided into subtypes. ...
... Type-Ib CPA fragmentation ( Figure 3B) is initiated at the side chain attached to the proline moiety by a [1,3] sigmatropic rearrangement of hydrogen to N-19, which generates the protonated ion species c attributed to the 13-membered cycle plus the side chain R 1 attached at C-5. R 1 can be isoleucine/ leucine or phenylalanine (hydroxyphenylalanine in 4) residues as indicated by c-type fragments at m/z 374 or 408 (m/z 424 in alkaloid 4), respectively. Another proton rearrangement promotes the macrocycle opening and the loss of a CO moiety (C-7). ...
... Figures S39 and S41). In both MS 2 spectra, peak m/z 408 (c, R 1 : C 7 H 7 ) suggests the presence of a phenylalanine residual chain as R 1 Figures S40 and S42). Due to the mass differences (14 amu), it was possible to confirm one extra CH 3 group in 17. ...
Ziziphus joazeiro Mart., popularly known as “juazeiro”, is a tree widely found in the northeast of Brazil. It is commonly used as an anti-inflammatory, antibacterial, antifungal, and analgesic agent. The stem extract exhibited, beside cytotoxic properties, substantial activity against the Gram-negative bacterium Allivibrio fischeri. UHPLC-ESI-Orbitrap-HR-MS analysis of the alkaloidal fraction of the crude methanolic stem extract of this species enabled the detection and putative identification of sixteen cyclopeptide alkaloids (CPAs), including four possibly new structures. According to the MS ² fragmentation analysis, from the sixteen identified CPAs, three possess a type-Ia1, one a type-Ia2, and twelve a type-Ib cyclopeptide alkaloid core. The structures of paliurine-C and -D were supported by NMR data.
... These structurally diverse and complex organic molecules fascinated medicinal chemistry researchers across the globe over the past six decades on account of their significant role in modern drug discovery and development [6]. Natural macrocycles of marine origin are common of fourteen to sixteen skeletal ring systems with different structure motifs, in which fourteen-membered macrocyclic frameworks are by far the most abundant [7,8]. As accounted earlier, oxygenated macrocyclic compounds possessing greater than sixteen-membered ring size could possess a lactone moiety, whereas thirteen and fourteenmembered analogous contain ether linkages. ...
Biochemical analysis of secondary metabolites of marine old-woman octopus Cistopus indicus (family Octopodidae) led to the identification of two sixteen-membered spiro-linked macrocyclic bislactones, named as cistobislactone A and cistobislactone B with unprecedented feature of henicos framework, based on extensive spectroscopic analyses. Cistobislactone B exhibited potential inhibition property against arachidonate 5-lipoxygenase (IC50 2.18 mM) than that demonstrated by cistobislactone A (IC50 2.54 mM) and standard non-steroidal anti-inflammatory agent ibuprofen (IC50 4.50 mM) thus signifying the higher anti-inflammatory activity of the cistobislactone B analogue. The studied macrocyclic bislactones exhibited promising antioxidant potential, in which cistobislactone B exhibited potential radical quenching (IC50 2.33 mM) and hydrogen peroxide scavenging (IC50 1.81 mM) activities that were proximal to the commercial anti-oxidant α-tocopherol (IC50 ~ 1.60 mM). This further reinforced its attenuation property against arachidonate 5-lipoxygenase. Considerably greater electronic properties coupled with balanced hydrophobicity of cistobislactone B could ascribe the superior ligand-receptor interfaces leading to its anti-inflammatory activity. Molecular docking analysis of cistobislactone B with 5-lipoxygenase recorded lesser docking score (−12.24 kcal mol−1) and binding energy (−11.24 kcal mol−1), which further supported its anti-inflammatory activity. Cistobislactone B, with six fold lesser value of inhibition constant (Ki 5.76 nM) towards 5-lipoxygenase than that displayed by cistobislactone A, could describe the superior protein-ligand interactions of the former. The undescribed cistobislactone B might be a potential natural anti-inflammatory lead to moderate the odds of inflammatory pathologies.
... [2] In addition, living systems produce chiral macrocycles [3] that, as secondary metabolites, engage in molecular recognition [4] to provide advantage to these organisms. [5] Evidently,n ature selects for asymmetric constructs that are conformationally preorganized but also electronically complementary to substrates for tuning the complexation entropy and enthalpy. [6] Alternatively,a rchetypal abiotic hosts [7] are symmetric macrocycles preferably obtained via one-pot syntheses. ...
The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket‐like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A‐to‐B and then AB‐to‐C Suzuki–Miyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) an enantioenriched basket with three benzene sides and each holding either tBu, Et, or Me esters, (b) both enantiomers of a so‐called “spiral staircase” basket with benzene, naphthalene, and anthracene groups surrounding the inner space, and (c) a photo‐responsive basket bearing one anthracene and two benzene arms.
... [2] In addition, living systems produce chiral macrocycles [3] that, as secondary metabolites, engage in molecular recognition [4] to provide advantage to these organisms. [5] Evidently,n ature selects for asymmetric constructs that are conformationally preorganized but also electronically complementary to substrates for tuning the complexation entropy and enthalpy. [6] Alternatively,a rchetypal abiotic hosts [7] are symmetric macrocycles preferably obtained via one-pot syntheses. ...
The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket‐like cavitands comprising of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene) and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A ‐to‐ B and then AB ‐to‐ C SuzukiMiyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) enantioenriched basket with three benzene sides and each holding either t ‐Bu, Et or Me esters, (b) both enantiomers of so‐called “spiral staircase” basket with benzene, naphthalene and anthracene groups surrounding the inner space and (c) photo‐responsive basket bearing one anthracene and two benzene arms.
... 4,5 Macrocyclic compounds (MCs)typically dened as organic compounds containing a ring of $12 atomsare a chemotype of particular current interest. 1,[6][7][8][9][10][11][12][13][14][15] Certain MCs appear to achieve superior ADME (Absorption, Distribution, Metabolism, and Excretion) properties compared to acyclic compounds of comparable MW. 7,11,12,[16][17][18][19][20] Moreover, MCs can make a large contact interface with their protein receptors, spanning widely spaced binding energy hot spots, 2 and consequently can bind topologically at sites such as are common at PPI interfaces. 1 Based on these observations, we, 2,3,21 and others, 1,6,8,11,12,14,16,[22][23][24] have hypothesized that MCs represent a privileged chemotype for binding and inhibiting PPI targets. ...
... 1,[6][7][8][9][10][11][12][13][14][15] Certain MCs appear to achieve superior ADME (Absorption, Distribution, Metabolism, and Excretion) properties compared to acyclic compounds of comparable MW. 7,11,12,[16][17][18][19][20] Moreover, MCs can make a large contact interface with their protein receptors, spanning widely spaced binding energy hot spots, 2 and consequently can bind topologically at sites such as are common at PPI interfaces. 1 Based on these observations, we, 2,3,21 and others, 1,6,8,11,12,14,16,[22][23][24] have hypothesized that MCs represent a privileged chemotype for binding and inhibiting PPI targets. The pharmaceutical utility of MCs is established by the fact that 82 have been approved as drugs, including 30 known to achieve systemic distribution when administered orally, with many others in clinical development. ...
... 2,7,35 As one approach to this problem, several studies have aimed to dene the structural and physicochemical properties of MC drugs. 1,2,7,14 For example, Over et al. compared 200 synthetic MCs from the Broad Institute's diversity-oriented screening library to all oral drugs and to the subset of oral drugs that violate the Ro5, to identify determinants of cell permeability and oral absorption. 7 Their work elucidated substructures, substituents, and molecular properties that impact permeability. ...
Macrocyclic compounds (MCs) are of growing interest for inhibition of challenging drug targets. We consider afresh what structural and physicochemical features could be relevant to the bioactivity of this compound class. Using these features, we performed Principal Component Analysis to map oral and non-oral macrocycle drugs and clinical candidates, and also commercially available synthetic MCs, in structure-property space. We find that oral MC drugs occupy defined regions that are distinct from those of the non-oral MC drugs. None of the oral MC regions are effectively sampled by the synthetic MCs. We identify 13 properties that can be used to design synthetic MCs that sample regions overlapping with oral MC drugs. The results advance our understanding of what molecular features are associated with bioactive and orally bioavailable MCs, and illustrate an approach by which synthetic chemists can better evaluate MC designs. We also identify underexplored regions of macrocycle chemical space.
... The most common naturally occurring macrocyclic scaffolds are 14-, 16-, and 18membered frameworks [1]. Over time, other classes of macrocyclic compounds have been synthesized and/or isolated from natural sources [2]. The co-ordination chemistry of macrocyclic scaffolds, such as these compounds became a major subdivision of inorganic chemistry, while intensive search for new types of macrocycles, and the number of their applications systematically, increased since their discovery [3]. ...
... Cr, Mn, Zn and Ru) [4]. With this class of complexes, we previousely published the synthesis and biological activities of two halocuprates complexes [Cu II (1,4,8,11- 2 •0.5(C 10 H 28 N 4 ) and Zn 2 (HPO 3 ) 3 •0.5(C 10 H 28 N 4 ) [7]. Mohan et al. reported on the synthesis of nanoparticulate Ni(OH) 2 films from a macrocyclic nickel(II) cyclam for the seek of Hydrogen production in microbial electrolytic cells [8]. ...
... The assymetric unit of the title compound (C 9 2 , as defined in the literature [21,22], is of 2.8·10 -4 , which indicates rather negligible distortion as behave the majority of the metals coordinated by only monodentate ligands [23]. ...
(C9H26N4)[SnCl6]Cl2∙2H2O has been synthesized in solution and its structure confirmed by single-crystal X-ray diffraction. It crystallizes in the monoclinic system, with space group P21/n (14), Z = 4, with refined cell parameters (Å,°) a= 10.7550(3), b= 15.3981(7), c= 13.8750(5), β= 103.095(3), V = 2238.04(15) ų. The 3D framework of the title compound is made of free molecules 1,4,7,10-tetraazacyclotridecane, [SnCl6], Cl atoms and water molecules, interacting through an intricate network of hydrogen-bonds and H...Cl interactions. The 1,4,7,10-tetraazacyclotridecane moiety is also confirmed by Raman spectroscopy. The Hirshfeld surface analysis of (C9H26N4)[SnCl6]Cl2∙2H2O is elucidated. Preliminary investigations of the electrochemical performance of the title compound as an active material in a Li-ion battery have also been carried out.
... Recently, macrocycles (herein defined as cyclic compounds with a ring size of 10 atoms or more) have gained increased importance in drug discovery because of their unique properties [6,[13][14][15][16][17]. Macrocycles may possess cell permeability better than expected by the "rule-of-five" [6,17,18], improved metabolic stability [11], enhanced binding properties to featureless binding sites [19], as well as the ability to disrupt protein-protein interactions [19][20][21][22]. ...
Macrocycles represent an important class of medicinally relevant small molecules due to their interesting biological properties. Therefore, a firm understanding of their conformational preferences is important for drug design. Given the importance of macrocycle-protein modelling in drug discovery, we envisaged that a systematic study of both classical and recent specialized methods would provide guidance for other practitioners within the field. In this study we compare the performance of the general, well established conformational analysis methods Monte Carlo Multiple Minimum (MCMM) and Mixed Torsional/Low-Mode sampling (MTLMOD) with two more recent and specialized macrocycle sampling techniques: MacroModel macrocycle Baseline Search (MD/LLMOD) and Prime macrocycle conformational sampling (PRIME-MCS). Using macrocycles extracted from 44 macrocycle-protein X-ray crystallography complexes, we evaluated each method based on their ability to (i) generate unique conformers, (ii) generate unique macrocycle ring conformations, (iii) identify the global energy minimum, (iv) identify conformers similar to the X-ray ligand conformation after Protein Preparation Wizard treatment (X-rayppw), and (v) to the X-rayppw ring conformation. Computational speed was also considered. In addition, conformational coverage, as defined by the number of conformations identified, was studied. In order to study the relative energies of the bioactive conformations, the energy differences between the global energy minima and the energy minimized X-rayppw structures and, the global energy minima and the MCMM-Exhaustive (1,000,000 search steps) generated conformers closest to the X-rayppw structure, were calculated and analysed. All searches were performed using relatively short run times (10,000 steps for MCMM, MTLMOD and MD/LLMOD). To assess the performance of the methods, they were compared to an exhaustive MCMM search using 1,000,000 search steps for each of the 44 macrocycles (requiring ca 200 times more CPU time). Prior to our analysis, we also investigated if the general search methods MCMM and MTLMOD could also be optimized for macrocycle conformational sampling. Taken together, our work concludes that the more general methods can be optimized for macrocycle modelling by slightly adjusting the settings around the ring closure bond. In most cases, MCMM and MTLMOD with either standard or enhanced settings performed well in comparison to the more specialized macrocycle sampling methods MD/LLMOD and PRIME-MCS. When using enhanced settings for MCMM and MTLMOD, the X-rayppw conformation was regenerated with the greatest accuracy. The, MD/LLMOD emerged as the most efficient method for generating the global energy minima.
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