RESUMO
The cis-stilbene, combretastatin A4 (CA4), is a potent microtubule targeting and vascular damaging agent. Despite promising results at the pre-clinical level and extensive clinical evaluation, CA4 has yet to be approved for therapeutic use. One impediment to the development of CA4 is an inherent conformational instability about the ethylene linker, which joins two aromatic rings. We have previously published preliminary data regarding structurally simplified biphenyl derivatives of CA4, lacking an ethylene linker, which retain anti-proliferative and pro-apoptotic activity, albeit at higher doses. Our current study provides a more comprehensive evaluation regarding the anti-proliferative and pro-apoptotic properties of biphenyl CA4 derivatives in both 2D and 3D cancerous and non-cancerous cell models. Computational analysis has revealed that cytotoxicity of CA4 and biphenyl analogues correlates with predicted tubulin affinity. Additional mechanistic evaluation of the biphenyl derivatives found that their anti-cancer activity is dependent on prolonged mitotic arrest, in a similar manner to CA4. Lastly, we have shown that cancer cells deficient in the extrinsic pathway of apoptosis experience delayed cell death following treatment with CA4 or analogues. Biphenyl derivatives of CA4 represent structurally simplified analogues of CA4, which retain a similar mechanism of action. The biphenyl analogues warrant in vivo examination to evaluate their potential as vascular damaging agents.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Bifenilo/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Mitose/efeitos dos fármacos , Estilbenos/química , Estilbenos/farmacologia , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Humanos , Células Jurkat , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Conformação Proteica , Estilbenos/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMO
Two substituted biaryl analogues of colchicine and combretastatin A4, readily available through a one-step, protecting group free Suzuki-Miyaura reaction were discovered to exhibit anticancer activity while simultaneously being of low cytotoxicity to noncancerous cell lines. The compounds were shown to initiate apoptosis selectively via a mechanism involving inhibition of tubulin polymerization.
