Tarade Daniel, Ma Dennis, Pignanelli Christopher, Mansour Fadi, Simard Daniel, van den Berg Sean, Gauld James, McNulty James, Pandey Siyaram
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
PLoS One. 2017 Mar 2;12(3):e0171806. doi: 10.1371/journal.pone.0171806. eCollection 2017.
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.
顺式二苯乙烯，康普瑞汀A4（CA4），是一种强效的微管靶向和血管损伤剂。尽管在临床前水平取得了有前景的结果并经过了广泛的临床评估，但CA4尚未被批准用于治疗。CA4开发的一个障碍是连接两个芳香环的乙烯连接基团存在固有的构象不稳定性。我们之前已经发表了关于CA4结构简化的联苯衍生物的初步数据，这些衍生物缺乏乙烯连接基团，尽管需要更高剂量，但仍保留抗增殖和促凋亡活性。我们目前的研究对二维和三维癌细胞及非癌细胞模型中联苯CA4衍生物的抗增殖和促凋亡特性进行了更全面的评估。计算分析表明，CA4和联苯类似物的细胞毒性与预测的微管蛋白亲和力相关。对联苯衍生物的进一步机制评估发现，它们的抗癌活性与CA4类似，依赖于延长的有丝分裂停滞。最后，我们表明，凋亡外源性途径缺陷的癌细胞在用CA4或类似物处理后细胞死亡延迟。CA4的联苯衍生物代表了结构简化的CA4类似物，它们保留了相似的作用机制。联苯类似物值得进行体内研究，以评估它们作为血管损伤剂的潜力。
