Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization

Abstract

J. Med. Chem. dimethylformamide (1 mL) was treated with 60% sodium hydride in oil (20 mg) for 20 min, and then with ethyl iodide (0.02 mL) for 20 min longer. The mixture was concentrated to dryness at 0.1 mm, taken up in ethyl acetate, washed with sodium bicarbonate solution, dried (Mg#O$, concentrated to dryness, and triturated with ether to afford the ester as an off-white solid, mp 110-118 OC (30 mg, 31%). Similarly, 3s was prepared from 3a i991,34, m 9 -2 5~ 2579 through the use of tert-butyl 4-(2-aminoethyl)phenylacetate.% An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in t.he five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitora of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-l-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (Sa). This substance was almost as potent as combretastatin A-4 (la), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a > 8a > 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (la), dihydrocombretastatin A-4 (IC), and transcombretastatin A-4 (lb). The relative potencies 5a > 8a > 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.

Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

“…Strong orthoeffects from substituents on phosphorus were already well known through the work of McEwen and co-workers 75, 76 and these had been extended to the Wittig reaction, although with conflicting results. 77,78 It was also known that Z-selectivity in stilbene synthesis could be induced by ortho-substituents with heteroatom lone pairs on the aldehyde 79,80 However, remarkably, we found that this latter Z-selectivity could be substantially augmented by an additional ortho-substituent on the benzylide, despite the fact that such a substituent would ordinarily lead to E-selectivity. This counter-intuitive cooperative effect was strong enough to be preparatively useful (Z/E up to 95:5) and the resulting Z-2,2'-disubstituted stilbenes have been used to good effect in synthesis by others.…”

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

“…We therefore could expect activity at the colchicine binding site of tubulin for suitably substituted benzoxepins. This type of benzoxepin structure will also avoid the inactivation observed for the conventional combretastatin derivatives, which is caused by cis-trans isomerism of the olefinic bond observed in vivo 23 . We have investigated the development of the benzoxepin type scaffold as a conformationally restricted analog for combretastatin, where the seven-membered oxygen containing ring forms a slightly flexible bridge on the ethylene bond linking the combretastatin rings A and B. Fifteen compounds have been synthesized and evaluated for specific antiproliferative activity in two human breast cancer cell lines, MCF-7 (estrogen receptor positive) and MDA-MB 231(estrogen receptor negative).…”

Synthesis and In Vitro Screening of Novel Heterocyclic Compounds as Potential Breast Cancer Agents

“…This compound was found to inhibit tubulin polymerization, and competitively inhibit the binding of radiolabeled colchicines to tubulin. Investigation of combretastatins revealed that combrestastatin A-4 was active against multidrug resistant (MDR) cancer cell lines (McGown, et al, 1990;Lin, et al, 1988 andCushman, et al 1991). Combretastatin (A-4), as well as its trans-isomer and a number of related substances, has been found to cause mitotic arrest in cells in culture at cytotoxic concentrations.…”