Benzannulated indoles as drug discovery templates. Efforts towards the total synthesis of a library of therapeutic candidates inspired by Cis-Trikentrin A
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Abstract
The herbindole and trikentrin indole alkaloids are a series of structurally related natural products, characterized by a 6,7-benzannulated indole core – a structural motif rarely observed in nature. Originally isolated from the Trikentrion flabelliforme, and Axinella sp. sponges, these compounds present as attractive targets for synthetic and medicinal chemists, due to their reported antibiotic, cytotoxic, and analgesic properties. Indeed, extensive efforts have been made since 1988 towards novel synthetic routes to the aforementioned natural products. Once accessed, analogues of the trikentrin indoles and herbindole present as ideal drug discovery templates due to their likelihood for bioactivity and high potential for synthetic diversification. Until recently, efforts towards the total synthesis of these deceptively simple herbindole and trikentrin indoles have proven these compounds to be challenging targets. Specifically, extensive substitution at the C4 and C5 positions without substitution at the easily accessible C2 and C3 positions have been of particular challenge to synthetic chemists. Additionally, these diastereomeric properties of the fused 6,7 dimethylcyclopentyl unit provides additional complexity to proposed synthetic routes. Many of these challenges have been alleviated through the discovery of a new class of reactive aryne intermediates. These intermediates allow for the generation of an in-situ 6,7-indole aryne, proving readily susceptible to selective annulation of the indole via [4+2] cycloaddition. Additionally, the tunable selectivity of the indole aryne generation allows for unaffected substituents at the C4 or C5 position, affording a wide variety of coupling reactions. Preliminary cell-based assays of herbindole and trikentrin indole analogue libraries have demonstrated promising anticancer, antiparasitic, and analgesic activity. Additionally, several key intermediates in the synthetic route towards these libraries have demonstrated newly discovered therapeutic value for a rare and aggressive cancer, sinonasal undifferentiated carcinoma (SNUC). Significant advances towards a more practical, accessible, and cost effective synthesis of these early intermediates have been made. Specifically, strategic eliminations of several toxic reagents and solvents (e.g. dichloromethane) as well as alternative synthetic approaches have been implemented. However, more work is needed in order to fully understand the structural activity relationship and maximize the therapeutic potential of these compounds. Recent advancements, described herein, enhance the practicality of the synthetic route towards a cis-Trikentrin A-inspired scaffold, with applications as a drug discovery template.
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Introduction -- High throughput screening of synthetic libraries -- Efforts towards improvements in the total synthesis of cis-trikentrin -- Expanded diversity in cis-trikentrin a analogue libraries -- Experimental section
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M.S.(Master of Science)