Ty Nancy, Dupeyre Grégory, Chabot Guy G, Seguin Johanne, Tillequin François, Scherman Daniel, Michel Sylvie, Cachet Xavier
Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8638 CNRS, Laboratoire de Pharmacognosie, 4 avenue de l'Observatoire, 75006 Paris, France.
Bioorg Med Chem. 2008 Aug 1;16(15):7494-503. doi: 10.1016/j.bmc.2008.06.002. Epub 2008 Jun 7.
6-Methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole (BPR0L075) (1) is a potent inhibitor of tubulin polymerization which exhibits both in vitro and in vivo activities against a broad spectrum of solid tumors. This compound was designed as a heterocyclic analogue of combretastatin A4 (CA-4), a natural stilbene derivative that disrupts the tumor vasculature and causes tumor regression. In the present work, we describe the design and synthesis of several new disubstituted analogues of 1, along with their biological evaluation as potential antivascular agents. Compound 13, bearing a hydroxyl group at the 7-position of the indole nucleus that mimics the hydroxyl group at the 3-position of the B-ring of CA-4, was identified as a potent inhibitor of tubulin polymerization and also as a cytotoxic agent against B16 melanoma cells at sub-micromolar concentration. In addition, compound 13 displayed marked morphological activity (rounding up) at nanomolar concentrations on endothelial cells (EA.hy 926 cells), which is indicative of potential antivascular activity. Interestingly, the corresponding 7-O-mesylate derivative 28 (an intermediate in the synthesis of 13), was also found active in cellular assays, although it was moderately active in the tubulin polymerization inhibition test. Finally, in order to better understand the SAR of disubstituted analogues of 1, two other position isomers (10 and 14), were synthesized and evaluated for their biological activities. It was noted that the 7-hydroxysubstituted analogue 13 was more potent than the 5-hydroxysubstituted analogue 10. In conclusion, this work has allowed the identification of biologically potent CA-4 analogues (13 and 28) and also contributes to a better understanding of the SAR of 1.
6-甲氧基-3-(3',4',5'-三甲氧基苯甲酰基)-1H-吲哚（BPR0L075）（1）是一种有效的微管蛋白聚合抑制剂，在体外和体内均对多种实体瘤具有活性。该化合物被设计为康普瑞汀A4（CA-4）的杂环类似物，CA-4是一种天然的芪衍生物，可破坏肿瘤血管并导致肿瘤消退。在本研究中，我们描述了几种新的1的二取代类似物的设计与合成，以及它们作为潜在抗血管生成剂的生物学评价。化合物13在吲哚核的7位带有一个羟基，该羟基模拟了CA-4的B环3位的羟基，被鉴定为微管蛋白聚合的有效抑制剂，并且在亚微摩尔浓度下对B16黑色素瘤细胞具有细胞毒性。此外，化合物13在纳摩尔浓度下对内皮细胞（EA.hy 926细胞）表现出明显的形态学活性（变圆），这表明其具有潜在的抗血管生成活性。有趣的是，相应的7-O-甲磺酸酯衍生物28（13合成中的中间体）在细胞试验中也被发现具有活性，尽管它在微管蛋白聚合抑制试验中活性中等。最后，为了更好地理解1的二取代类似物的构效关系，合成了另外两种位置异构体（10和14）并对其生物学活性进行了评价。值得注意的是，7-羟基取代的类似物13比5-羟基取代的类似物10更有效。总之，这项工作鉴定出了具有生物学活性的CA-4类似物（13和28），也有助于更好地理解1的构效关系。
