Design and Synthesis of Sugar Phosphates and Phosphonates for Inhibition of Tuberculosis Maltosyltransferase

• Main Authors: Wei-Hsin Hsu, 許瑋心
• Other Authors: Jim-Min Fang
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/4b9e49

碩士 === 國立臺灣大學 === 化學研究所 === 105 === Tuberculosis, a disease caused by bacterial pathogens Mycobacterium tuberculosis, was regarded as under control in the past decades. However, the multi-drug-resistant tuberculosis (MDR-TB) and extensively-drug-resistant tuberculosis (XDR-TB) have emerged to become a serious global health crisis. In 2015, there were an estimated 10.4 million new TB cases worldwide, including nearly a half million cases of MDR-TB. Although there are anti-MDR-TB drugs, it is still needed to develop new drugs targeting different TB proteins for treatment of the XDR-TB patients. GlgE is a maltosyltransferase that uses maltose-1-phosphate as the substrate. GlgE involves in a four-step pathway for the production of α-glucan from trehalose, an essential process for mycobacterial survival. Inhibition of GlgE causes accumulation of maltose-1-phosphate, and triggers the self-poisoning of M. tuberculosis. According to the toxic effect and synthetic lethal pathway, GlgE becomes an appealing drug target. As no effective GlgE inhibitor has been discovered, we thus designed some potential GlgE inhibitors by mimicking the structure of maltose-1-phosphate, the GlgE substrate. Our initial aim is to synthesize the sugar phosphate and phosphonate compounds 16 and 18 as GlgE inhibitors against M. tuberculosis. We have searched several approaches to synthesize the D-glucosyl phosphate 16 by using allyl, TBDMS and acetyl protecting groups. The acetyl protected intermediate 57 was successfully synthesized from D-glucose as the starting material. We also converted compound 57 to phosphate esters 58 and 59 with phenyl and trichloroethyl as the R groups, respectively. The sugar phosphate 16 was finally achieved by two steps of deprotection from phosphate ester 59. Various protecting groups, including the acetyl, benzoyl and TBDMS groups, have been used in the synthetic approach to compound 18. We have prepared the 3,6-TBS protected glucose 90 from acetal 34. Nevertheless, Wittig reaction of compound 90 still failed. We propose another novel approach to compound 18 without using Wittig reaction.