Review of Cytotoxic CA4 Analogues that Do Not Target Microtubules: Implications for CA4 Development

Background: One of the most studied anti-cancer compounds of the last several decades is the microtubule targeting agent and cis-stilbene, combretastatin A4 (CA4). Despite promising results at the pre-clinical level, future clinical use of CA4 as a monotherapy is in question due to metabolic vulnerability and conformational instability. Objective: Thus, medicinal chemists have focused on synthesizing derivatives with improved pharmokinetic profile. One common strategy has been the incorporation of the ethylene linker into a ring system, thus preventing the isomerization of CA4 into the virtually inactive trans-isomer. Although many structurally stable and potent analogues of CA4 have been designed and synthesized, several analogues have been discovered to possess anti-proliferative properties seemingly independent of microtubule targeting. The presence of such analogues suggests that CA4 may also possess nonmicrotubule targets, which reveals the necessity for future structure activity relationship studies and optimization of any non-microtubule targeting. Furthermore, analogues of CA4 not inhibiting microtubule polymerization can no longer be assumed to be inactive. Conclusion: Future clinical development of the CA4 pharmacophore requires that attention should be paid to abnormal CA4 analogues, which appear to retain cytotoxicity independent of canonical microtubule inhibition.