Naphthalene-based heterosteroidal molecules

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Estrogens, a category of the steroidal hormone system having an aromatic ring, bind with and activate the estrogen receptors promoting a variety of physiological responses such as bone maturation, blood lipid profile, neuroprotective effects, reproductive functions and breast cell proliferation. Heterosteroids are man-made polycyclic steroidal systems where one or more carbons are replaced by heteroatom(s). Owing to the structural and topological similarity with natural steroids, heterosteroids are a subject of intense research that reports syntheses of new congeners and unveils interesting and useful properties that they possess. However, synthesis of heterosteroids bearing key functional groups and stereochemistry have not be explored. Dr. Amitabh Jha's research team has established expertise in synthesis of biologically relevant compounds and medicinal chemistry. The potential of Dr. Jha's research findings on curcumin analogs and selective estrogen**receptor modulators attracted significant attention, including interest from Paraza Pharma, Inc., a Canadian company that specializes in integrated drug discovery services. Early discussions between Paraza and the Jha Group led to an NSERC Engage and subsequently a MITACS Accelerate grant. In this proposed project, methods will be developed and optimized for the synthesis of heteropolycylic analogs of estrogen. Over a period of 24 months, our goal is to develop asymmetric synthetic methodologies for seven naphthalene-based heterosteroids resembling estrogen. The designed strategy involves the innovative use of reactive intermediates such as N-acyliminium ions, azaquinone methides, donor-acceptor cyclopropanes, etc. in a cascade fashion to assemble the polycyclic core structure. This research will provide direct benefit to Paraza as it is expected to provide them with a focused library of close heterocyclic congeners of estrogen for bioevaluation. The results of this study will strengthen Paraza's research pipeline to include drug development for diseases related to modulation of steroidal hormone receptors. This project will also enable significant training opportunities for HQP interested in organic synthesis.