Pentalinonsterol, Scytonemide A, and Structural Analogues as Mechanistic Probes for the Exploration of Antileishmanial/Anti-Cancer Activities
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Date
2015-05
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The Ohio State University
Abstract
Global health issues such as leishmaniasis and cancer have a major effect on the world today. The current therapies for these diseases are limited by their costs, efficacies, emerging resistance, and toxicities. In an effort to circumvent these deleterious problems researchers are looking to discover new drugs that may overcome these obstacles. Despite recent advances in high throughput screening and combinatorial chemistry, small molecule natural products or their naturally inspired derivatives account for 59% of all of the new drugs since 1981. Natural products and their derivatives are responsible for 64% of new antiparasitic drugs and 79.8% of the anti-cancer approved drugs. Due to the proven effectiveness of these compounds as drugs it is no wonder why scientists continue to search for novel secondary metabolites that are biologically active. It is this search that led to the discovery of pentalinonsterol (from the roots of Pentalinon adrieuxii) and scytonemide A (from the cyanobacteria Scytonema hofmanni) which have potent antileishmanial and anticancer activities, respectively. However, the isolation of these natural products led to only very low quantities of these compounds that could be obtained from their respective sources (1.2 mg from 900g of P. andrieuxii dried roots and 1.2 mg from 8 liters of S. hofmanni cell culture). Based on the limited supply of the lead compounds, synthetic routes must be developed and optimized to generate more of these compounds and facilitate in vitro and in vivo assays as well as mechanism of action studies. The studies will help to determine the respective pharmacophores for each natural product required for biological activity and improve the pharmacokinetic and pharmacological properties for further therapeutic application. Herein is described the process by which these compounds and their analogues were discovered, isolated, and synthesized with the intent to develop new drugs that are more potent and less cytotoxic than the current therapies.
Description
First place at the Denman Undergraduate Research Forum (2014)
Honorable Mention at the Denman Undergraduate Research Forum (2015)
Honorable Mention at the Denman Undergraduate Research Forum (2015)
Keywords
Natural Products, Total Synthesis, Structure-Activity Relationship