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.
Eur J Med Chem. 2024 Jan 5;263:115794. doi: 10.1016/j.ejmech.2023.115794. Epub 2023 Sep 6.
The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents.
小分子微管聚合抑制剂的合成和评估仍然是开发癌症治疗新治疗剂的有前途的方法。天然产物秋水仙碱和 combretastatin A-4（CA4）激发了针对位于微管二聚体β亚基上的秋水仙碱结合位点的重大药物发现活动，但到目前为止，这些努力尚未在人类癌症患者中产生一种批准用于癌症治疗的药物。秋水仙碱结合位点的兴趣增加了，因为发现一组秋水仙碱结合位点试剂具有双重功能，既是有效的抗增殖剂，又是有效的血管破坏剂（VDA）。我们之前的研究导致发现和开发了一种 2-芳基-3-芳酰基-吲哚类似物（OXi8006），该类似物抑制微管聚合，并对多种人类癌细胞系表现出低纳摩尔 IC 值的抑制作用。从 OXi8006 合成的水溶性磷酸盐前药盐（OXi8007）在癌症的小鼠模型中显示出有前途的血管破坏活性。为了进一步扩展结构-活性关系相关性，合成了一系列 6-芳基-3-芳酰基-吲哚类似物，并评估了它们对微管聚合的抑制作用和对人类癌细胞系的细胞毒性。该小文库中的几种结构不同的分子是微管聚合的强抑制剂，并且对 MCF-7 和 MDA-MB-231 人类乳腺癌细胞具有细胞毒性。最有前途的类似物之一（KGP591）导致 MDA-MB-231 细胞明显的 G2/M 期阻滞，破坏 MDA-MB-231 细胞中的微管结构和细胞形态，并在划痕试验中显示出对 MDA-MB-231 细胞迁移的显著抑制。从其母体酚前体合成的磷酸盐前药盐 KGP618，在体内评估时，在 BALB/c 小鼠的肾癌细胞（RENCA-luc）的原位模型中，对生物发光信号显示出显著降低，表明 VDA 有效。该系列中最活跃的化合物有望成为抗癌治疗剂。
