Design and Synthesis of C-2’ Substituted 3-Phenylindoles as Rad51 Inhibitors

• Main Authors: Hsin-Siao Shih, 施欣孝
• Other Authors: Jiann-Jyh Huang
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/71454647033642388327

碩士 === 國立嘉義大學 === 應用化學系研究所 === 102 === Rad51 is a crucial protein of the homologous recombination (HR) pathway in repairing of DNA double-strand breaks and interstrand cross-links. This protein is encoded by the gene which is highly similar to bacterial RecA and yeast Rad51, and extremely conserved in most eukaryotes. Rad51 activity increases the HR rate that induces the abnormal DNA replication and cell proliferation in many cancers, including breast and chronic myeloid cancers. In this thesis, I synthesized a series of C-2’ substituted 3-phenylindole derivatives as Rad51 inhibitors. Indole (3) served as the staring material and was iodinated at its C-3 position to give 3-iodoindole (4) in 84% yield. Protecting the N1H functionality in 4 by phenylsulfonyl chloride gave compound 5 in 65% yield. Borylation of 5 gave 1-(phenylsulfonyl)-3-indolylboronic acid pinacol ester (6) in 64% yield, which was then cross-coupled with various aryl iodides or bromides by Suzuki coupling to give C-2’ substituted 3-phenylindole 8a–g and 16–24 in 42–81% yields. Among the new compounds I have synthesized, 8a displayed the most potent antiproliferative activities, with IC50 of 12.1, 5.51, 6.50, and 5.51 μM for K562, Hela, MDA-MB-213, and MDA-MB-468 cancer cells, respectively. In comparison of lead compound IBR2 and reference compound B02, compound 8a showed 2–4-fold improved potency.