設計合成以麥芽糖為修飾基底的亞胺糖衍生物作為分支結核桿菌麥芽糖轉移酶抑制劑

Abstract

結核病(Tuberculosis, TB)是由結核分枝桿菌(Mtb)複合群引起的流行病。現行標準都治計畫是徹底根治肺結核疾病的治療方針，但由於需長時間服用多種藥物以因應細菌的抗藥性，導致病人容易產生嚴重服用藥物副作用。因此，迫切需要針對抗藥性和藥物敏感性結核病的新一代的治療藥物。麥芽糖轉移酶(GlgE)是一種結核分枝桿菌生長必需酶和潛在治療結核病藥物的抑制標的，它可以催化聚合α-葡聚醣(α-D-glucan)細胞壁成分，藉由轉移連接麥芽糖1-磷酸(M1P)單元延長形成α-1,4-葡聚醣鏈，基於催化機制，我們鎖定設計合成以麥芽糖為修飾基底的亞胺糖作為結核菌的GlgE抑制劑。我們合成這些抑制劑的原理主要是在模擬催化機制麥芽糖基質半椅式(half-chair)過渡構型，以及變旋中心(anomeric center)具有正電荷性質的亞胺糖，藉此增加抑制分子在GlgE催化活性中心的電荷作用力。將胍基(guanidinium group)和修飾官能基連接到亞胺麥芽糖上(iminomaltose)，預期能與GlgE催化活性位點中的Asp394和Glu423的側鍊末端酸基產生電荷作用力。在本論文中，我們是以麥芽糖構型的亞胺糖作為關鍵前驅物，製備多種麥芽糖構型亞胺糖衍生物作為Mtb GlgE抑制劑。Tuberculosis (TB) is an epidemic disease caused by the Mycobacterium tuberculosis (Mtb) complex. Standard four-combined anti-TB treatment has long been used with a great success. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB in many parts of the world leads to a diversification of drug regimens and to the use of drugs that are more toxic per se and more likely to interact with others. The discovery of anti-TB drugs with lower toxicities and shorter treatment times will help to reduce further growth of drug-resistant TB in the population. Mtb GlgE, a recently identified (1-4)-α-D-glucan:phosphate-D-maltosyltransferase involved in α-glucan biosynthesis, is an essential enzyme and has been validated as a potential target for TB drug discovery and development. Based on the catalytic mechanism, we hypothesized that the Asp 394 and Glu 423 represent key catalytic residues as the nucleophile and general acid in the enzymatic mechanism, respectively. In this thesis, we focus on the design and synthesis of N-substituted malto-configured iminosugar as transition-state inhibitors for GlgE by replacing the endocyclic oxygen atom of glycosides with a nitrogen atom. We anticipate that the resulting tertiary ammonium moiety will mimic the partial positive charge accumulation at the anomeric carbon of the substrate and form a strong charge-charge interaction with the Asp 394 nucleophile. The confluence of these interactions would therefore promote reasonable inhibition of all GlgE homologues. Using the malto-configured iminosugar as a key precursor, we have prepared various N-substituted malto-configured iminosugar derivatives against Mtb GlgE.