10.1016/j.bmc.2016.12.010
The study focuses on the synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids, which are designed to inhibit tubulin polymerization and induce apoptosis in cancer cells. These compounds were synthesized by modifying the combretastatin pharmacophore, replacing ring B with benzothiazole scaffolds and incorporating triazole and tetrazole rings to restrict the cis configuration of the olefinic bond. The synthesized compounds were evaluated for their antiproliferative activity on selected cancer cell lines, and the structure-activity relationship was developed. The most potent compounds demonstrated effects comparable to combretastatin A-4 (CA-4), a known tubulin-binding ligand. The study aimed to develop new molecules with improved properties, such as better aqueous solubility and reduced toxicity, to target microtubules and disrupt cancer cell division. The chemicals used in the study include various substituted anilines, p-nitrobenzoylchlorides, Lawesson's reagent, and other reagents for the synthesis of the target compounds, as well as CA-4 as a reference compound for biological evaluation. The purpose of these chemicals was to create a series of novel tubulin inhibitors that could potentially be developed into anticancer drugs.
10.1039/b702411h
The study presents a concise synthetic route to the anti-cancer agents combretastatin A-4 and DMU-212 using the Ramberg–B?cklund reaction. Combretastatin A-4, isolated from the African tree Combretum caffrum, is a potent inhibitor of tubulin polymerization, while DMU-212 is a synthetic analogue with cancer chemoprotective activity. The synthesis of combretastatin A-4 begins with the coupling of thiol 13, prepared from 3,4,5-trimethoxybenzyl alcohol using Lawesson’s reagent, and bromide 14, using potassium hydroxide in ethanol. The resulting sulfide is oxidized with m-chloroperoxybenzoic acid to form sulfone 12. The Ramberg–B?cklund reaction, carried out under various conditions (Meyers, Chan, and Franck), converts sulfone 12 into the stilbene intermediate 15, which is then desilylated to yield combretastatin A-4. The study also explores the synthesis of other combretastatin analogues, including (E)- and (Z)-2012, using similar procedures. The Ramberg–B?cklund reaction is further applied to prepare DMU-212 from sulfone 29, derived from 4-methoxybenzyl mercaptan and bromide 17. The study highlights the efficiency and stereoselectivity of the Ramberg–B?cklund reaction in synthesizing these anti-cancer stilbenes and provides insights into the reaction's scope and limitations.
