Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents

Abstract

A series of stilbenes has been prepared and tested for cytotoxicity in the five human cancer cell lines A-549 non-small cell lung, MCF-7 breast, HT-29 colon, SKMEL-5 melanoma, and MLM melanoma. The cis stilbenes 6a-f proved to be cytotoxic in all five cell lines, with potencies comparable to that of combretastatin A-4. These cytotoxic compounds were all potent inhibitors of tubulin polymerization. The corresponding trans stilbenes 7b-f were inactive as tubulin polymerization inhibitors and were significantly less cytotoxic in the five cancer cell lines. In the dihydro series, 8b, 8c, and 8f were inactive as tubulin polymerization inhibitors, while 8a, 8d, and 8e were less active than the corresponding cis compounds 6a, 6d, and 6e. The lack of tubulin polymerization inhibitory activity and cytotoxicity displayed by the phenanthrene 23b, which was synthesized as a conformationally rigid analogue of the lead compound 1, indicates that the activity of the stilbenes is not due to a totally planar conformation. Similarly, inactivity of the conformationally restricted analogue 26 suggests that the biologically active conformation of 1a resembles that of the cis alkene 1. Additional inactive compounds prepared include the benzylisoquinoline series 28-32 as well as the protoberberines 38 and 39. Shortening the two-carbon bridge of 1a to a one-carbon bridge in the diphenylmethane 20 resulted in a decrease in cytotoxicity and tubulin polymerization inhibitory activity. Although the corresponding benzophenone 18 was as active as 1a as a tubulin polymerization inhibitor, it was less cytotoxic than 1a, and the benzhydrol 19 was essentially inactive. With the exception of the amide 15c, which displayed low antitubulin activity, all of the phenylcinnamic acid derivatives 14a-c and 15a-f were inactive in the tubulin polymerization inhibition assay. The acid 14b and the ester 15a were cytotoxic in several of the cancer cell cultures in spite of their inactivity as tubulin polymerization inhibitors.

The interaction with tubulin of a series of stilbenes based on combretastatin A-4

“…Why only these two agents (4b,7b) cause this block is not known, particularly as no disruption of the intracellular microtubular network was observed even at 50 gIM. In general, these studies are in agreement with the report by Cushman et al (1992) that the cis-methyl and -ethyl derivatives (3a,4a) inhibit tubulin assembly. This present study further characterises the interaction of agents of this type with tubulin.…”

“…(d) The 3'-hydroxyl group has a relatively small effect on binding to tubulin (Cushman et al, 1992). (e) The 4'-methoxy group of combretastatin A-4 (1) can be replaced with small hydrophobic groups while still retaining significant activity against tubulin.…”

“…Similarly, the effects of these agents on the growth of A2780 human ovarian tumour cells and P388 mouse leukaemia cells, together with their multidrug-resistant sublines, were studied in vitro. This study is complementary to that of Cushman et al (1992). …”

Tubulin-interactive stilbene derivatives as anticancer agents

“…SAR studies of CA-4 have underlined that the presence of a 3,4,5-trimethoxy-substituted A-ring and 4-methoxy-substituted B-ring separated by a double bond with the cis-configuration are fundamental for anti-proliferative activity [3]. It has also been reported that the 3-hydroxy group on the B-ring is not necessarily determinant for potent activity [63,64]. Cushman et al [64] synthesized a series of 4'-methoxy-3,4,5-trimethoxy-cis-stilbene derivatives where the methoxy group in the B-ring was replaced with a variety of other substituents.…”

“…It has also been reported that the 3-hydroxy group on the B-ring is not necessarily determinant for potent activity [63,64]. Cushman et al [64] synthesized a series of 4'-methoxy-3,4,5-trimethoxy-cis-stilbene derivatives where the methoxy group in the B-ring was replaced with a variety of other substituents. The most potent tubulin polymerization inhibitor, 4'-methoxy-3,4,5-trimethoxy-cisstilbene, influenced tubulin assembly with an IC 50 of 2.0 M comparable to CA-4.…”