Phenstatin analogues with non-aromatic attachments in place of the B-ring

Amanda Oswald

Abstract


Cancer is a deadly disease caused by mutations in normal working cells; affecting millions of people each year.1 Chemotherapy and surgeries are costly, necessitating the need for noninvasive and cost effective anti-cancer drugs.2 Natural compounds like colchicine, combretastatin (CA-4), and phenstatin are examples of tubulin inhibiting drugs. These types of drugs attach to colchicine binding sites of microtubulin during the process of mitosis and halt cell division. The tubulin inhibiting drugs block nutrients and oxygen to the mutated cell therefore disrupting the cell’s normal processes.3 This research project aims to produce four new derivatives of phenstatin. The project focuses on the binding characteristics, like torsional and steric strain, of the new derivatives in the colchicine pocket. The phenstatin molecule will have a phenothiazine A-ring and a 3-, 4-, 7-, or 8- membered cyclic non-aromatic B-ring. The expectation is that the new derivatives will fit in the colchicine-binding site due to the hydrophobic interactions in the pocket due to the phenothiazine and non-aromatic ring attachments. Phenothiazine based molecules were tested by another research group and found their phenstatin derivatives produced anti-cancer effects towards tumor cells. The challenge of synthesizing phenstatin analogues containing 3- and 4- membered non-aromatic rings will be due to their large torsional and steric strain. The case of synthesizing phenstatin analogues with 7- and 8- membered non-aromatic rings might be easier due to the low torsional strain. The synthesis for the desired phenstatin derivatives will be the focus of this presentation.

 

 

1) American Cancer Society. Cancer Facts & Figures 2015. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/ (accessed November 2015).

 

2) American Cancer Society. Treatment Types. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/ (accessed November 2015).

 

3) Flynn, B. L. Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties. Journal of Medicinal Chemistry, 2011, 54, 6014-6027.


Keywords


Phenstatin Analogues, Microtubulin-targeting agents, Anti-cancer Molecules

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