Synthesis of dihydronaphthalene analogues inspired by combretastatin A-4 and their biological evaluation as anticancer agents

• Published in: MedChemComm 2018-10, Vol.9 (10), p.1649-1662
• Main Authors: Maguire, Casey J, Chen, Zhi, Mocharla, Vani P, Sriram, Madhavi, Strecker, Tracy E, Hamel, Ernest, Zhou, Heling, Lopez, Ramona, Wang, Yifan, Mason, Ralph P, Chaplin, David J, Trawick, Mary Lynn, Pinney, Kevin G
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antitumor agents; Aromatic compounds; Bearing; Biocompatibility; Bioluminescence; Blood flow; Cancer; Carbon 13; Colchicine; Crystallography; Cytotoxicity; Disruption; Doppler effect; Evaluation; Health care facilities; High-performance liquid chromatography; In vivo methods and tests; Inhibitors; Intermediates; Liquid chromatography; Lungs; Natural products; NMR; Nuclear magnetic resonance; Organic chemistry; Phosphates; Polymerization; Salts; Toxicity; Tubulin; Tumor cell lines; Tumors; Ultrasound; X-ray crystallography
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/C8MD00322J

The natural products colchicine and combretastatin A-4 ( ) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. A water-soluble phosphate prodrug salt of (referred to as ) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs). Through a long-term program of structure activity relationship (SAR) driven inquiry, we discovered that the dihydronaphthalene molecular scaffold provided access to small-molecule inhibitors of tubulin polymerization. In particular, a dihydronaphthalene analogue bearing a pendant trimethoxy aryl ring (referred to as ) and a similar aroyl ring (referred to as ) were potent inhibitors of tubulin polymerization (IC = 1.0 and 1.2 μM, respectively) and displayed low nM cytotoxicity against human cancer cell lines. In order to enhance water-solubility for evaluation, the corresponding phosphate prodrug salts ( and , respectively) were synthesized. In a preliminary study in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc, a 99% reduction in signal was observed with bioluminescence imaging (BLI) 4 h after IP administration of (200 mg kg ) indicating reduced tumor blood flow. In a separate study, disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor was observed by color Doppler ultrasound following administration of (15 mg kg ).