Date of Award

2021-05-01

Degree Name

Doctor of Philosophy

Department

Chemistry

Advisor(s)

Yaoqiu Zhu

Abstract

Organic chemistry is an exploratory world in which chemists translate their knowledge by creating new molecules and explore their biological and physical properties. For the past three years, our research has been focused on organic synThesis and chemical biology to solve challenges in this area. Two major approaches have been faced: First, the chemical synThesis of the active metabolite of antithrombotic prodrug Plavix (clopidogrel). Clopidogrel (CPG) has been widely used as an antithrombotic prodrug, which undergoes extensive metabolism in patients; among it, only a trivial portion is converted through a series of cytochrome P450 (CYP)-catalyzed thiophene degradation to form active metabolite (M13-H4), a P2Y12R antagonist. Despite more than twenty-yearâ?? prevalent use clinically, CPG has demonstrated prominent drawbacks including high levels P2Y12R and to overcome the prominent therapeutic resistances of CPG by chemical synThesis of M13-H4, metabolite which has been considered unstable and highly reactive. In our pursuit of the synthetic access to M13-H4 under mild conditions, which can be the key to solving these long-overdue conundrums, we discovered new metabolites that support an alternative pathway in the CPG bioactivation and can correlate with the dose-clinical response relationship and identify CPG as a clinical hydrogen sulfide donor. In addition, the stereoselective synThesis of M13-H4, which can be flexibly converted to its releasable forms for drug development, abrogate the bioactivation dependence of CPG efficacy and can elucidate the molecular mechanism of P2Y12R activation and inhibition, and can help to overcome the clinical resistances associated with CPG treatment. Secondly, a short-step bioinspired asymmetric total synThesis of complex marine terpenoid (-)-pavidolide B and its anticancer diastereomers. The total synThesis of complex natural products is arguably the most challenging subject in chemistry and often requires not only a daunting number of steps but also complex experiments to perform these steps. In addition, the synthetic routes we develop often lack the flexibility for structural modification to satisfy the needs of modern drug discovery. Inspired by terpenoid biosynThesis, we have developed a novel annulation strategy of carbanion cascade reaction to accomplish a 4-step facile asymmetric total synThesis of (â??)-pavidolide B, a complex anticancer marine diterpenoid with a 6/5/5/7 fused-ring system and seven contiguous stereocenters. The key step is a tandem intramolecular Michael addition of an ester intermediate, which constructs two fused 5-membered rings and five stereocenters in a highly selective fashion in just one step. The annulation strategy can be flexible modified to prepare pavidolide B diastereomers to aid the exploration of the anticancer mechanism of the natural product as well as channel future SAR studies for discovering potent and selective chemotherapeutics. Finally, a facile, robust, and efficient method to replace the oligolactone core and to circumvent the direct cyanization with TMSCN for the synThesis of antiviral drug Remdisivir was achieved from a Diels-Alder. The approach is strategically distinct from the first and second-generation routes and could further enable the synThesis of Remdesivir and other small-molecule therapeutics.

Language

en

Provenance

Recieved from ProQuest

File Size

129 p.

File Format

application/pdf

Rights Holder

Elkin Libardo Romero

Available for download on Sunday, May 28, 2023

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