Epothilone A-D and their thiazole-modified analogs as novel anticancer agents

Abstract

Starting from epothilone A±D (1a±2b) obtained by large scale fermentation of the myxobacterium Sorangium cellulosum the thiazole side-chain was extensively modi®ed by substitution, oxidation and replacement. Metallation afforded the C-19 carbanion 4 which was quenched by various carbon and heteroatom electrophiles to give C-19 substituted epothilones 5. Thiazole N-oxides 9 were obtained by treatment of 2a and 2b with m-chloroperbenzoic acid and rearranged by acetic anhydride to 21-acetoxy epothilones 10. Cleavage of epothilones A and B with ozone gave methyl ketones 11 from which carbonyl derivatives 12, 13, 14, and aldol condensation products 16 were prepared. Similarly vinyl boronic acid 17 was obtained and transformed by Suzuki coupling or iodination/Stille coupling to aryl and heteroaryl analogs 15.Scheme 1 Biosynthesis of epothilones A and B (2a and 2b) by epoxidation of epothilones C and D (1a and 1b) and their hydroxylation to epothilones E and F (3a and 3b) by Sorangium cellulosum.

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

“…Therefore, 13-hydroxy-and 12-hydroxyellipticine are the products of the activation pathway of ellipticine metabolism. 12-Hydroxyellipticine is formed in two ways, one by direct oxidation, and one by Polonowski rearrangement 40,41 of ellipticine N 2 -oxide 27 . Therefore, the formation of 12-hydroxyellipticine or ellipticine N 2 -oxide, followed by its spontaneous rearrangement to 12-hydroxyellipticine, are two pathways leading to the formation of the same reactive species binding to DNA.…”

Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity

“…Later, a block-mutant strain was added, supplying epothilones C and D. 17 Early one-step transformations were performed with epothilone A, including mono-and diacylation of the 3,7-dihydroxy groups, Swern oxidation to 3,5-and 5,7-diketones, and borohydride reduction of the C5 ketone to a 1:1 mixture of epimeric alcohols. 165, 166 12,13-Dihydro-epothilone C was formed selectively with diimine, whereas catalytic reduction produced complex mixtures because of hydrogenolysis of the allylic ester moiety. H 2 SO 4 ), chlorohydrins (HCl), or rearranged 14membered lactones (TFA, BF 3 OEt 2 ).…”

“…Ring-closing olefin metathesis afforded, for example, the alkyne analog 16 of epothilone C along with the expected stereoisomer at C12/C13 (Scheme 21.6). Suzuki coupling of 20 required reactive iodo compounds, such as iodo benzene; otherwise, it was transformed by N-iodosuccinimide (NIS) to the corresponding iodovinyl epothilone and introduced in Stille couplings, 166 as described by Nicolaou et al 119,120 Initially, modification of the thiazole ring other than by replacement seemed hardly possible in the presence of the sensitive functional groups in the macrocycle. 171 More direct modifications of the linker group C16,C17 were catalytic hydrogenation, epoxidation followed by reduction to a 16-hydroxyl group, 164 and its elimination to a C16 exomethylene derivative.…”

Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAFV600E inhibitors

“…Based on the studies generalized, thiophene and thiazole group manifest a wide range of pharmaceutical of antibacterial, anti-inflammatory and antiviral property when exposed to the native compounds. [22,23] With the development of scientific research, more reports reveal anticancer activities of the compounds containing thiophene and thiazole group, [24][25][26] which inhibits BRAF kinase activity. As a consequence, the combined substructures (thiophene and thiazole group) without wrecking their original effective characteristics, might exhibit synergistic effects to improve anticancer activities [27][28][29] .…”