FR901464 is a natural product that was isolated in 1996 by the Fujisawa Pharmaceutical Company as reported by Nakajima et al. It was found to have an intriguing biological profile and exhibited potent anti-proliferative activity against a panel of human cancer cell lines.
Total synthesis and extensive structure-activity-relationship studies have lead to the potent analogs meayamycin and meayamycin B.
Our synthetic strategy breaks the natural product down into three intermediates that can be coupled together for a convergent synthesis.
One of the biological pathways of this class of molecules was determined to be the regulation of the MCL-1 gene, which encodes for both the anti-apoptotic Mcl-1L and pro-apoptotic Mcl-1S proteins. A hallmark of cancer is the up-regulation of anti-apoptotic proteins which allows for cell survival and proliferation. Upon treatment with meayamycin B, expression of Mcl-1L decreases and expression of Mcl-1S increases, leading to cell death via apoptosis.
Current research in this project focuses on determining the metabolic weak points and generating analogs to improve the PK performance.
Representative Publications
Osman, S., Albert, B.J., Wang, Y., Li, M. Czaicki, N.L., & Koide K. Chem.-Eur. J. 2011, 17, 895–904.
Osman, S., Waud, W.R., Gorman, G.S., Day, B.W. & Koide, K. Med. Chem. Commun. 2011, 2, 38–43.
Albert, B.J., McPherson, P.A., O’Brien, K., Czaicki, N.L., DeStefino, V., Osman, S., Li, M., Day, B.W., Grabowski, P.J., Moore, M., Vogt, A. & Koide, K. Mol. Cancer Ther. 2009, 8, 2308–2318.
Albert, B.J., Sivaramakrishnan, A., Naka, T., Czaicki, N.L. & Koide, K. J. Am. Chem. Soc. 2007, 129. 2648–2659.
Albert, B.J., Sivaramkrishnan, A., Naka, T. & Koide, K J. Am. Chem. Soc. 2006, 128. 2792–2793.