This proposal represents a continuation of work initiated under NIH AREA grant CA67236-02, which began July 1, 2001 and will end July 31,2004. The previous proposal focused on using 3-substituted or 2,3- disubstituted beta-chloroenals as key synthons for the regioselective preparation of pyrroles, which could function as precursors to appropriate, bioactive, marine natural products or might exhibit interesting bioactivity of their own. Alkaloids, which belong to this rapidly growing family of pyrrole containing marine natural products, exhibit anti-tumor, anti-HIV, immunomodulatory and multidrug resistance (MDR) reversal activities and are under current investigation by a significant number of research groups. Interestingly, studies in our group during the last several years indicate that further elaboration at the 5 position of these 2,3,4-trisubstituted pyrroles is quite challenging, with the exception of the bromination at the 5 position with NBS. In addition, the desire to create a rapid and diverse group of analogs for biological evaluation prompted us to consider some previous work in our laboratory. We have demonstrated that symmetrical vinamidinium salts can be readily and efficiently prepared and condensed with glycinate esters to give 2-carboalkoxy-4- substituted pyrroles in high yields. Our new strategy involves the electrophilic substitution of the 2,4- disubstituted pyrroles at the 5 position. This is followed by bromination with NBS at the 4-position and then a cross-coupling reaction (Suzuki or Heck type) to give the tetrasubstituted core, which can be further elaborated to the desired pyrroles. The targets of this methodology will initially be the marine natural products Polycitone A and B, Rigidins A-D, Permethyl Storniamide, Ningalin A and their analogs. In this manner, a large, flexable and regioselective array of pyrroles can be rapidly assembled. All of the target molecules, their precursors and their analogs will subsequently be bioassayed by collaborators and/or the NCI. Mode of action and structure activity relationships will also be examined (in conjunction with collaborators) as part of this project.
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