Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents

Abstract

A new library of small molecules with structural features resembling combretastatin analogs was synthesized and evaluated for anticancer activity against a panel of 60 human cancer cell lines. Three novel acrylonitrile analogs (5, 6 and 13) caused a significant reduction in cell growth in almost all the cell lines examined, with GI50 values generally in the range 10–100 nM. Based on the structural characteristics of similar drugs, we hypothesized that the cytotoxic activity was likely due to interaction with tubulin. Furthermore, these compounds appeared to overcome cell-associated P-glycoprotein (P-gp)-mediated resistance, since they were equipotent in inhibiting OVCAR8 and NCI/ADR-Res cell growth. Given that antitubulin drugs are among the most effective agents for the treatment of advanced prostate cancer we sought to validate the results from the 60 cell panel by studying the representative analog 6 utilizing prostate cancer cell lines, as well as exploring the molecular mechanism of the cytotoxic action of this analog.

Combretastatins: More Than Just Vascular Targeting Agents?

“…P-gp is the most characterized member of the ABC family. It is well established from numerous sources that the combretastatins are not substrates for the P-gp and thus offer a therapeutic advantage over other clinically used MTAs such as the taxanes and the vinca alkaloids, which are known P-gp substrates (Shirai et al, 1998;Gwaltney et al, 2001;Xu et al, 2008;Greene et al, 2010;Lee et al, 2010;Romagnoli et al, 2012;Penthala et al, 2013). Similarly, the combretastatins demonstrated potent activity in cancer cells overexpressing BCRP .…”

Synthesis, structure–activity relationship, and mechanistic investigation of lithocholic acidamphiphiles for colon cancer therapy

“…1 Many small molecule and antibody based therapeutics have been engineered and developed for cancer therapy to target this disease effectively. 2 Apart from genetic reasons, prolonged high consumption of western-type diet augments risk of colon cancer in majority of patients. Increase uptake of fatty diets need extensive recirculation of bile acids for its digestion.…”

l-Proline catalyzed one-step synthesis of 4,5-diaryl-2H-1,2,3-triazoles from heteroaryl cyanostilbenes via [3+2]cycloaddition of azide

“…11 Recently, we reported the synthesis of a variety of heterocyclic cyanstilbene analogs as anti-cancer agents. 12 In the view of the promising biological activity of the triazole analogs and in continuation of our research work on cyanostilbene analogs (Fig 1; 2 and 3a ) 12 as novel anticancer agents, we focused on the incorporation of a triazole bridge unit between the two aromatic ring systems of such molecules by chemical modification of cyanostilbene moiety (Scheme 1). Unlike compounds 1-3a , the resulting 4,5-disubstituted-2 H -1,2,3-triazole analogs cannot undergo cis-trans isomerization, providing molecules with greater stability (e.g.…”

“…12 This reaction predominantly forms the trans -isomer ( 3a ) which slowly converts to the respective cis -isomer ( 2 ) in organic solvents; more rapid trans to cis conversion takes place in the presence of protic solvents and on exposure to light. To avoid this geometrical isomerism we sought to lock the geometry of cyanostilbenes ( 3a-i ) by converting them to their corresponding 1,2,3-(2 H )-triazole analogs ( 6a-i ) by reaction with NaN 3 /DMSO in the presence of a Lewis base such as L-proline (Scheme 2).…”