Development of a Lewis acidic transition-metal promoted cyclization of a bis-guanidinium allenyl unit leading toward tricyclic cores resembling saxitoxin will be undertaken. This will probe the reactivity profile of an otherwise unknown bis-guanidinium substituted allene insofar as its reactivity towards cyclizations is concerned. A modular approach is presented that allows for access to various substitution patterns and ring-sizes closely resembling saxitoxin for further structure-activity relationship (SAR) studies agains human sodium voltage (NaV) channels. Subtypes of these NaV channels have been linked to the mechanism of pain, which has sparked heavy interest in analgesic drug development. The lack of crystal structure data for the transmembrane proteins, however, hinders rational drug design. Such SAR studies with unnatural derivatives of saxitoxin against these channels are extremely limited or unknown and would help to elucidate the architecture of these proteins for future therapeutics. Current estimates conclude that ~30% of the U.S. population is afflicted with chronic pain; therefore, further understanding of these transmembrane proteins is paramount. Completion of the proposed research will achieve the following: 1) A better understanding of the reactivity profile in C?N bond construction of an allene unit using guanidine as nucleophiles; 2) Access to a metal carbenoid species in situ which has broad synthetic utility in the chemistry community, an alternative route that avoids potentially explosive diazo compounds; 3) Potential platform to access bis-guanidinium tricyclic cores with various ring-sizes and substitution patterns; 4) Correlate structure-activity relationships of saxitoxin-like scaffolds against the human NaV1.7 ion channel aiding in their structural elucidation for future rational design in analgesics of therapeutic value.
The proposed research herein will aid in the synthesis of a chemical library of compounds resembling the scaffold of saxitoxin, a highly neurotoxic compound, yet a fundamentally valuable tool within chemical biology as a molecular probe. Through the development of a new modular method to quickly access a library of saxitoxin-like cores, further structure-activity relationship studies against mammalian sodium voltage channels will be undertaken. Probing the reactivity of these channels, recently linked to the mechanism of pain, will play a role in the development of future therapeutics treating chronic pain, thereby improving the human health of 25-30% of the U.S. population currently affected.
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