Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland.
Department of Inorganic and Analytical Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland.
Eur J Med Chem. 2018 Jan 20;144:797-816. doi: 10.1016/j.ejmech.2017.11.050. Epub 2017 Dec 12.
A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC values of 0.86, 1.05, and 0.85 μM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents.
设计并合成了一系列新型的 combretastatin A-4 (CA-4) 硫代衍生物，这些衍生物包含不同的分子核心，分别为α-苯基肉桂酸（核心 1）、（Z）-二苯乙烯（核心 2）、4,5-二取代恶唑（核心 3）和 4,5-二取代 N-甲基咪唑（核心 4），作为顺式限制类似物。这些化合物是通过一种平行虚拟筛选方案选择的，该方案包括基于 CA-4 类似物的精心合成方案生成虚拟组合文库。选择的化合物针对六种人类癌细胞系（A431、HeLa、MCF7、MDA-MB-231、A549 和 SKOV）和两种人类非癌细胞系（HaCaT 和 CCD39Lu）进行了抗增殖活性评估。此外，还评估了测试化合物对体外微管蛋白聚合的抑制作用。在所研究的系列中，恶唑桥接类似物表现出最强的抗增殖活性。化合物 23a、23e 和 23i 分别以 0.86、1.05 和 0.85μM 的 IC 值有效地抑制微管蛋白聚合。与氧类似物 23j 相比，硫代衍生物 23i 对微管蛋白聚合的抑制作用提高了 5 倍。在细胞周期分布和促凋亡活性方面，表现出最佳细胞毒性和抗微管蛋白活性的化合物 23e 和 23i 进一步进行了研究。化合物 23e 在 A431、HaCaT、HeLa、MCF-7、MDA-MB-231 和 SKOV-3 细胞中以与 CA-4 相当的程度将细胞周期阻滞在 G2/M 期，统计学上显著。在与 23i 孵育的 HeLa 和 SKOV-3 细胞中，观察到 G2/M 期的浓度依赖性阻滞。ELISA 测定和 Annexin V-FITC/PI 双重染色证明了 23e 和 23i 在 A431、HaCaT、MCF-7、MDA-MB-231 和 SKOV-3 中的促凋亡作用。结果表明，化合物 23e 和 23i 可能作为研究更有效的抗癌药物的新型先导化合物。
