application): The overall goal of this research program is to reduce the number of chemical steps and thereby to improve the cost effectiveness of the GMP chemical manufacture of squalamine lactate (MSI-1256F). Squalamine is an antiangiogenic and anticancer agent currently in Phase I human safety trials for advanced malignancies and may have broad applicability, notably in combination chemotherapy with various cytotoxic agents. Positive results with any or all of the research approaches described here will directly impact on the cost of goods, which is currently limiting in the investigation of this agent in human clinical trials. The manufacture of MSI-1256F presently requires 16 chemical steps. Process improvements including a reduced number of chemical steps and improved product yield will be achieved by exploring three approaches: (a) microbial biotransformations which introduce important functional groups at stereocenters, (b) pioneering of a new chemical route to a key intermediate using fewer steps, and (c) feasibility testing for scale-up of steps in the new chemical route. The results of these studies will be integrated to launch improved syntheses of GMP grade MSI-1256F for use in later stage clinical trials.
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| Kinney, W A; Zhang, X; Williams, J I et al. (2000) A short formal synthesis of squalamine from a microbial metabolite. Org Lett 2:2921-2 |
