Date of Award

December 2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

M. Mahmun Hossain

Committee Members

M. Mahmun Hossain, James Cook, Arsenio Pacheco, Mark Dietz, Xiaohua Peng

Keywords

Asymmetric Synthesis, HDAC Inhibitors, Hydroxyacrylates, Microtubule Inhibitor, Phase-Transfer-Catalysis

Abstract

PART I: A CONCISE ASYMMETRIC SYNTHESIS OF MICROTUBULE INHIBITOR TRYPROSTATIN B

Tryprostatin (TPS) A and B, microtubule inhibitor, are the members of a family of prenylated Trp-Pro diketopiperzine alkaloids. These two natural products were isolated in 1995 from the fermentation broth of Aspergillus fumigatus BM939 by Osada and coworkers. TPS and related diketopiperazine containing compounds such as phenylahistins, spirotryprostatins, and cyclotryprostatins are inhibitors of the mammalian cell cycle. They prevent cell cycle progression at the G2/M phase through a unique mechanism consisting of inhibiting the interaction between microtubule assisted proteins (MAP-2) and the C-terminal end of tubulin. TPS A and B hold great potential because they were found to have inhibitory activity on the cell cycle progression of mouse tsFT210 cells with minimum inhibitory concentration (MIC) values of 16.4 μM for TPS A and 4.4 μM for TPS B, respectively. The poor abundance of TPS A and B in nature and long synthetic procedure have limited their development as viable anti-cancer therapeutics. On the other hand, their interesting biological activity and simple structure have drawn attention from the synthetic community, and several total syntheses have been reported. Herein, a concise and efficient total synthesis of tryprostatin B was described. The key step was the preparation of a diprenylated gramine salt where the prenyl group was incorporated at the 2-position of the indole moiety by direct lithiation of the Boc-protected gramine. We also developed and optimized the asymmetric phase-transfer-catalyzed reaction with diprenylated gramine salt to provide the C2-prenyl tryptophan intermediate resulting in 93% enantiomeric excess (ee) and 65% yield. The total synthesis of tryprostatin B was done in six steps with 35% overall yield.

PART II: SYNTHESIS AND BIOLOGICAL ASSESSMENT OF HISTONE DEACETYLASE INHIBITORS

Histone acetylation and deacetylation in eukaryotic cells is delicately maintained by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These enzymes are responsible for the modifications to chromatin structures and regulation of transcription. In general HAT activity leads to an increase in gene transcription through the opening of the chromatin framework by adding acetyl groups. In contrast, HDAC catalyze the removal of the acetyl groups on lysine residues located on the NH2 terminal tails of core histones, which leads to gene repression by chromatin condensation. As a result, inhibition of HDAC activity can result in a general hyperacetylation of histones, which is followed by the transcriptional activation of certain genes through relaxation of the DNA conformation. These posttranslational modifications are essential for the regulation of many cellular processes. Natural product-based HDAC inhibitors such as vorinostat (SAHA), romidepsin (FK228) are usually very potent, moderately isoform-selective, but are often associated with poor solubility, ineffective against solid tumors and excessive cytotoxicity. To overcome these limitations of the market drugs, a group of HDAC inhibitors were synthesized based on market drug FK228. One of our synthetic compounds was found to be active against class I HDAC and possibly effective against Alzheimer’s disease. Further investigations, including microsomal assays and pharmacokinetic studies, are currently underway.

PART III: ACID CATALYZED REACTIONS OF AROMATIC KETONES WITH ETHYL DIAZOACETATE

3-Hydroxyacrylates or 3-oxo-esters are useful precursors for synthesizing important biologically active and pharmaceutically important compounds due to their multiple functionality and preferable substrate scope. These synthons are also applied for the construction of quaternary carbon center containing compounds due to the presence of an active prochiral center. In 1998 and later in 2004, our group reported the unprecedented reactions of aromatic aldehydes with ethyl diazoacetate (EDA) in the presence of the iron Lewis acid and the Brønsted type acid, respectively. This novel reaction formed 3-hydroxyacrylates by an unusual 1, 2-aryl shift. In this project, we extended this method for less reactive aromatic ketones with EDA using Brønsted acid catalyst to produce the 3-hydroxyacrylates. 3-hydroxyacrylates and 3-oxo-esters were isolated from the reactions by 1,2-aryl/alkyl shifts. The products from these reactions can be applied to make all-carbon quaternary center containing natural products.

Available for download on Wednesday, December 23, 2020

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