ChemInform Abstract: Antibiotics from Gliding Bacteria. Part 77. Epothilone A and B ‐ Novel 16‐Membered Macrolides with Cytotoxic Activity. Isolation, Crystal Structure, and Conformation in Solution.

Abstract

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Characterizing the Epothilone Binding Site on β-Tubulin by Photoaffinity Labeling: Identification of β-Tubulin Peptides TARGSQQY and TSRGSQQY as Targets of an Epothilone Photoprobe for Polymerized Tubulin

“…Subsequently Canales et al 17 conducted STR and TR-NOESY NMR studies with dimeric and polymerized tubulin and found that the epothilone binding site and the epothilone conformation are in complete agreement with the crystal structure of dimeric tubulin. 22 Figure 4 shows five three-dimensional structures of epothilone conformers that have been observed or proposed: (a) epothilone A bound to zinc-stabilized α,β-tubulin sheets (PDB code 1TVK); 14 (b) epothilone A in aqueous medium in the presence of α,β-tubulin monomers; 25 (c) derived from the crystal structure of epothilone B bound to cytochrome P450 (PDB code 1Q5D); 28 (d) epothilone A X-ray structure crystallized from dichloromethane/petroleum ether; 29 (e) the conformation of epothilone A from X-ray crystallography (PDB code 4I50). 22 While there is some similarity among the structures with regard to the conformation of the macrocycles that are shown in Figure 4, it is also clear that the orientations of the epoxide and the C15 thiazole-containing side chain are quite different.…”

Conformational Preferences of Natural and C3-Modified Epothilones in Aqueous Solution

“…1,2 However, in contrast to taxol, epothilones are not (or only very poor) substrates for the P-gp efflux pump and, therefore, exhibit virtually identical potency against drugsensitive and many drug-resistant tumor cell lines (including taxol-resistant lines) in vitro. 3 In addition, epothilones are considerably more water-soluble than taxol, 4 thus enabling the use of less problematic formulation vehicles for clinical applications. Based on this favorable biological and physicochemical property profile, epothilones represent promising leads for the development of new anticancer drugs.…”

Interrogating the Bioactive Pharmacophore of the Latrunculin Chemotype by Investigating the Metabolites of Two Taxonomically Unrelated Sponges

“…Their basic structural motif consists of a macrolide 1,3 fused to a tetrahydropyran containing a 2-thiazolidinone side chain. Compound 1 also shares a carbon skeleton with the anti-cancer active epothilone A,3 obtained from cultures of the terrestrial myxobacterium, Sorangium cellulosum 4,5. The sustained attention given to the latrunculins can be attributed to three factors–a unique mixed biogenesis from PKS/NRPS,a,3 their potent actin inhibition properties,2,6 and their potent cytotoxicity against cancer cell lines 7.…”

“…The two lead compounds of this series are latrunculin A ( 1 ) and latrunculin B ( 2 ), originally isolated from the Red Sea sponge Negombata magnifica (old genus designation Latrunculia ). , Their basic structural motif consists of a macrolide 1,3 fused to a tetrahydropyran containing a 2-thiazolidinone side chain. Compound 1 also shares a carbon skeleton with the anticancer active epothilone A, obtained from cultures of the terrestrial myxobacterium Sorangium cellulosum . , The sustained attention given to the latrunculins can be attributed to three factors: a unique mixed biogenesis from PKS/NRPS, , a Abbreviations: DFT, density functional theory; PKS/NRPS, polyketide synthase/nonribosomal peptide synthetase; MAE, mean absolute error; colon 38, murine colon adenocarcinoma; L1210, murine lymphocytic leukemia; CFU-GM, murine bone marrow; HCT-116, human colorectal carcinoma; MDA-MB-435, human breast cancer; SRB, sulforhodamine B; A10, rat smooth muscle; DTP, developmental therapeutics program. their potent actin inhibition properties, , and their potent cytotoxicity against cancer cell lines . In comparison to the many other common natural product actin inhibitors latrunculin A is the most widely used small molecule molecular probe.…”

“…Compound 1 also shares a carbon skeleton with the anticancer active epothilone A, 3 obtained from cultures of the terrestrial myxobacterium Sorangium cellulosum. 4,5 The sustained attention given to the latrunculins can be attributed to three factors: a unique mixed biogenesis from PKS/NRPS, a,3 their potent actin inhibition properties, 2,6 and their potent cytotoxicity against cancer cell lines. 7 In comparison to the many other common natural product actin inhibitors 8 latrunculin A is the most widely used small molecule molecular probe.…”