Antineoplastic Agents. 445. Synthesis and Evaluation of Structural Modifications of (Z)- and (E)-Combretastatin A-4

Abstract

A series of cis- and trans-stilbenes related to combretastatin A-4 (1a), with a variety of substituents at the 3'-position of the aryl B-ring, were synthesized and evaluated for inhibitory activity employing six human cancer cell lines (NCI-H460 lung carcinoma, BXPC-3 pancreas, SK-N-SH neuroblastoma, SW1736 thyroid, DU-145 prostate, and FADU pharynx-squamous sarcoma) as well as the P-388 murine lymphocyte leukemia cell line. Several of the cis-stilbene derivatives were significantly inhibitory against all cell lines used, with potencies comparable to that of the parent 1a. All were potent inhibitors of tubulin polymerization. The corresponding trans-stilbenes had little or no activity as tubulin polymerization inhibitors and were relatively inactive against the seven cancer cell lines. In terms of inhibition of both cancer cell growth and tubulin polymerization, the dimethylamino and bromo cis-stilbenes were the most potent of the new derivatives, the latter having biological activity approaching that of 1a. As part of the present study, the X-ray crystal structure of the 3'-O-phosphate of combretastatin A-4 (1b) was successfully elucidated. Compound 1b has been termed the "combretastatin A-4 prodrug", and it is currently undergoing clinical trials for the treatment of human cancer patients.

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

“…[14] However, potent fluoro-containing analogues of 4 are known [27]. Ring B with a bromide substituent was reported to have moderate activity in a range of cell lines [28]. In our series, this compound was not as potent as either the lead compound 13 or 26.…”

Novel cis-restricted β-lactam combretastatin A-4 analogues display anti-vascular and anti-metastatic properties in vitro

“…In vivo, its water-soluble prodrug, CA-4P, induces a rapid and selective shutdown of tumour blood flow and subsequently tumour regression (7,8) and thus the compound is currently undergoing clinical trials as a vascular-disrupting agent. The therapeutic efficacy of CA-4 is limited by its intrinsic instability rendering it readily isomerisable to its inactive trans-conformation (15)(16)(17). Therefore, non-isomerisable CA-4 analogues have been developed to provide more stable alternatives to CA-4.…”

“…1. Only the cis-configuration of CA-4 is biologically active (15). The spatial arrangement between its 3,4,5-trimethyloxyphenyl A-ring and 3-hydroxy-4-methoxyphenyl B-ring are crucial to its functionality and ability to interact with tubulin (15)(16)(17).…”

“…Only the cis-configuration of CA-4 is biologically active (15). The spatial arrangement between its 3,4,5-trimethyloxyphenyl A-ring and 3-hydroxy-4-methoxyphenyl B-ring are crucial to its functionality and ability to interact with tubulin (15)(16)(17). However, the cis-isomer is intrinsically unstable and readily isomerises to the more thermodynamically stable but inactive trans-configuration (15).…”

“…The spatial arrangement between its 3,4,5-trimethyloxyphenyl A-ring and 3-hydroxy-4-methoxyphenyl B-ring are crucial to its functionality and ability to interact with tubulin (15)(16)(17). However, the cis-isomer is intrinsically unstable and readily isomerises to the more thermodynamically stable but inactive trans-configuration (15). Cis-trans isomerisation can be triggered by heat, light and protic media thus lowering the therapeutic efficacy of the agent.…”