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. 2023 Sep 7;92:117400. doi: 10.1016/j.bmc.2023.117400. Epub 2023 Jun 29.
The oxetane functional group offers a variety of potential advantages when incorporated within appropriate therapeutic agents as a ketone surrogate. OXi8006, a 2-aryl-3-aroyl-indole analogue, functions as a small-molecule inhibitor of tubulin polymerization that has a dual mechanism of action as both an antiproliferative agent and a tumor-selective vascular disrupting agent. Replacement of the bridging ketone moiety in OXi8006 with an oxetane functional group has expanded structure activity relationship (SAR) knowledge and provided insights regarding oxetane incorporation within this class of molecules. A new synthetic method using an oxetane-containing tertiary alcohol subjected to Lewis acid catalyzed conditions led to successful Friedel-Crafts alkylation and yielded fourteen new oxetane-containing indole-based molecules. This synthetic approach represents the first method to successfully install an oxetane ring at the 3-position of a 2-aryl-indole system. Several analogues showed potent cytotoxicity (micromolar GI values) against human breast cancer cell lines (MCF-7 and MDA-MB-231) and a pancreatic cancer cell line (PANC-1), although they proved to be ineffective as inhibitors of tubulin polymerization. Molecular docking studies comparing colchicine with the OXi8006-oxetane analogue 5m provided a rationale for the differential interaction of these molecules with the colchicine site on the tubulin heterodimer.
氧杂环丁烷官能团在适当的治疗剂中作为酮替代物时具有多种潜在优势。OXi8006 是一种 2-芳基-3-芳酰基吲哚类似物，作为微管聚合的小分子抑制剂发挥作用，具有双重作用机制，既是增殖抑制剂，又是肿瘤选择性血管破坏剂。用氧杂环丁烷官能团替代 OXi8006 中的桥接酮部分，扩展了结构活性关系 (SAR) 知识，并深入了解了该类分子中氧杂环丁烷的掺入。使用含有氧杂环丁烷的叔醇的新合成方法，经过路易斯酸催化条件，成功进行了 Friedel-Crafts 烷基化反应，并得到了 14 种新的含氧杂环丁烷的吲哚基分子。这种合成方法代表了成功在 2-芳基-吲哚体系的 3-位上安装氧杂环丁烷环的第一种方法。尽管这些类似物被证明不能作为微管聚合抑制剂，但它们对人乳腺癌细胞系 (MCF-7 和 MDA-MB-231) 和胰腺癌细胞系 (PANC-1) 表现出很强的细胞毒性 (微摩尔 GI 值)。比较秋水仙碱与 OXi8006-氧杂环丁烷类似物 5m 的分子对接研究为这些分子与微管蛋白二聚体上的秋水仙碱结合部位的不同相互作用提供了依据。
