Structure Guided Design, Synthesis, and Biological Evaluation of Oxetane-Containing Indole Analogues

• Published in: Bioorganic & medicinal chemistry 2023-09, Vol.92, p.117400, Article 117400
• Main Authors: Ren, Wen, Vairin, Rebecca, Ward, Jacob D., Francis, Ricardo, VanNatta, Jenny, Bai, Ruoli, Tankoano, Pouguiniseli E., Deng, Yuling, Hamel, Ernest, Trawick, Mary Lynn, Pinney, Kevin G.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Cell Line, Tumor; Cell Proliferation; Colchicine - pharmacology; Drug Screening Assays, Antitumor; Friedel-Crafts alkylation; Humans; Indoles - chemistry; Inhibition of tubulin polymerization; Molecular Docking Simulation; Molecular Structure; Oxetane; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - pharmacology
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2023.117400

[Display omitted] •Synthetic installation of the oxetane moiety to quaternary carbons by Friedel–Crafts.•Synthesis of a series of oxetane-containing indole analogs with novel skeletons.•Oxetane indole analogues demonstrated low µM cytotoxicity (human cancer cell lines).•Molecular docking studies provided insight regarding colchicine site orientation. 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 GI50 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.