Vairin Rebecca, Tamminga Caleb, Shi Zhe, Borchardt Christian, Jambulapati Jayaram, Bai Ruoli, Wanniarachchi Hashini, Bueno Lorena, Hamel Ernest, Mason Ralph P, Trawick Mary Lynn, Pinney Kevin G
Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX 76798-7348, United States.
Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States.
Bioorg Med Chem. 2025 Feb 1;118:117981. doi: 10.1016/j.bmc.2024.117981. Epub 2024 Nov 7.
Inhibitors of tubulin polymerization represent a promising therapeutic approach for the treatment of solid tumors. Molecules that bind to the colchicine site are of interest as they can function with a dual mechanism of action as both potent antiproliferative agents and tumor-selective vascular disrupting agents (VDAs). One such example is a 2-aryl-3-aroyl-indole molecule (OXi8006) from our laboratory that demonstrates potent inhibition of tubulin polymerization and strong antiproliferative activity (cytotoxicity) against a variety of human cancer cell lines. A water-soluble prodrug OXi8007, synthesized from OXi8006, demonstrates in vivo disruption of tumor-associated microvessels in several tumor types (mouse models). The molecular framework of OXi8006 inspired a series of fourteen new 2-aryl-3-aroyl-indole analogues that incorporated various functional group modifications on both the indole core and the aroyl ring. Electron withdrawing and donating groups at the mono-substituted 3' position and the di-substituted 3',5' positions were all accommodated while maintaining inhibition of tubulin polymerization (IC < 5 μM), with several analogues demonstrating activity comparable to OXi8006 and the benchmark natural product combretastatin A-4 (CA4). Preliminary structure-activity relationship (SAR) studies were further enhanced by molecular docking to predict possible colchicine site interactions. Two analogues (KGP366 and KGP369) previously synthesized in our laboratory were re-synthesized using a somewhat modified route to increase synthetic efficiency and were subsequently converted to their corresponding water-soluble phosphate prodrug salts to evaluate their efficacy as VDAs. Administration of the prodrug salt (KGP415) of KGP369 caused significant reduction in bioluminescence signal from an orthotopic kidney tumor (RENCA-luc) in BALB/c mice, indicative of VDA activity. Collectively, these new functionalized indole-based analogues have extended SAR knowledge related to the colchicine binding site, and the most biologically active analogues hold promise for continued development as pre-clinical candidates for cancer therapy.
微管蛋白聚合抑制剂是治疗实体瘤的一种有前景的治疗方法。与秋水仙碱结合位点结合的分子备受关注，因为它们可以作为强效抗增殖剂和肿瘤选择性血管破坏剂（VDA）发挥双重作用机制。我们实验室的一种2-芳基-3-芳酰基吲哚分子（OXi8006）就是这样一个例子，它对微管蛋白聚合有强效抑制作用，并且对多种人类癌细胞系具有很强的抗增殖活性（细胞毒性）。由OXi8006合成的水溶性前药OXi8007在几种肿瘤类型（小鼠模型）中显示出对肿瘤相关微血管的体内破坏作用。OXi8006的分子框架启发了一系列14种新的2-芳基-3-芳酰基吲哚类似物，这些类似物在吲哚核心和芳酰环上都进行了各种官能团修饰。在单取代的3'位和二取代的3',5'位上的吸电子和供电子基团都能被容纳，同时保持对微管蛋白聚合的抑制作用（IC<5μM），有几种类似物显示出与OXi8006和基准天然产物康普瑞汀A-4（CA4）相当的活性。通过分子对接预测可能的秋水仙碱结合位点相互作用，进一步加强了初步的构效关系（SAR）研究。我们实验室之前合成的两种类似物（KGP366和KGP369）使用略有修改的路线重新合成，以提高合成效率，随后转化为它们相应的水溶性磷酸前药盐，以评估它们作为VDA的功效。KGP369的前药盐（KGP415）给药后，BALB/c小鼠原位肾肿瘤（RENCA-luc）的生物发光信号显著降低，表明具有VDA活性。总的来说，这些新的功能化吲哚基类似物扩展了与秋水仙碱结合位点相关的SAR知识，最具生物活性的类似物有望作为癌症治疗的临床前候选药物继续开发。
