Synthesis, Molecular Docking, and Antiproliferative Activity of C11‐Modified Cryptolepine and Norcryptolepine Analogues

Abstract Natural indoloquinoline alkaloids e.g. cryptolepine and norcryptolepine have attracted considerable interest, due to their broad‐‎spectrum biological activities, particularly their anticancer properties. However, their clinical application remains limited by issues e.g. poor solubility, suboptimal bioavailability, and low selectivity toward cancer cells. To overcome these limitations, and enhance their therapeutic potential, we designed and synthesized a novel series of cryptolepine analogues through structural modification at the C11 position. The strategy adopted for synthesis is straight and efficient through installation of amino alkylamino groups at C11 position of indoloquinoline core and modifying terminal amino group into corresponding acyclic or cyclic carbamides, thiocarbamides and sulfonamides. All compounds were characterized for their anticancer activity against MCF‐7, Hep‐G2, HCT‐116 human cancer cells and normal cell line (BJ‐1); showed potent antiproliferative activities in vitro. Compounds coded 8, 14, 15b, and 15c exhibited the lowest IC50 values against examined cancer cell lines. For HCT‐116 human colorectal carcinoma cells, indicates that four compounds (15b, 15c, 13, and 14) exhibit superior cytotoxic activity, with IC50 values of (0.54, 1.59, 3.37, and 3.50 µM), with selectivity index (SI) of (78.3, 14.40, ‎5.20, 1.30) toward cancer cells respectively, compared to staurosporine, which has an IC50 of 9.28 µM and SI of ‎1.40.