Total Syntheses of Mycobactin Analogues as Potent Antimycobacterial Agents Using a Minimal Protecting Group Strategy

Abstract

Mycobactins are a family of iron sequestering agents (siderophores) biosynthesized as growth promoters by mycobacteria including Mycobacterium tuberculosis. They are important siderophores with high affinity and specificity for Fe(III) due to the chemical nature of their component chelating functional groups. The parent compounds and their synthetic analogues can be used for studies of natural iron uptake mechanisms. It was hypothesized by Snow and co-workers that alternate and modified mycobactin analogues might serve as antagonists of mycobacterial growth and be of important therapeutic value. Efficient syntheses of four different analogues are presented. Dramatic improvements on formation of amide and ester bonds were achieved using water soluble carbodiimide (EDC‚HCl)-mediated couplings in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) as an additive. Using HOAt over other traditional coupling additives provided significant enhancement of the reaction rate of the desired coupling reactions and minimized side reactions. Further simplifications were made possible by minimizing the use of protecting groups during the syntheses. In fact, coupling components in the presence of free hydroxamic acids and a free phenolic hydroxyl group proceeded in excellent yields. Biological studies indicated that the resulting synthetic analogues effect moderate to high inhibition of the growth of M. tuberculosis H37Rv.(1) Brown, D. U.S. Tuberculosis Cases Decline as Disease Increases Worldwide.

Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

“…Without purification, the resulting amine salt was reacted with Boc 2 O in the presence of excess NaHCO 3 to provide orthogonally protected lysine 4 in excellent yield. Hydrogenation of the Z-protecting group revealed the amine, which was then coupled to the known oxazoline acids 5a,b (27) by the action of EDC/HOAt. Completion of the syntheses began with the LiOH-mediated saponification of the methyl esters of 6a,b.…”

“…Solution Phase Synthesis of DDM-The strategy was based on previous syntheses by which protected forms of the cobactin and mycobactic acid are coupled, deprotected, and acylated (23)(24)(25)(26)(27). The synthesis reported here relies on production of deoxymycobactic acid and deoxycobactin (see Fig.…”

“…These products coupled to form the protected peptide backbone and then deprotected and coupled to the acyl side chain to yield dideoxymycobactin. This strategy was potentially expeditious because problems with certain key intermediates, reaction methods, and extraction procedures had been solved during prior, successful efforts to synthesize mycobactin (23)(24)(25)(26)(27). In fact, it might have been possible that mycobactin or other intermediates leading to the synthesis of mycobactin were sufficient to stimulate CD1a-restricted T cells, obviating the need to produce DDM for immunological studies.…”

Siderophore-Based Iron Acquisition and Pathogen Control

“…Following the establishment of its total chemical synthesis, synthetic mycobactin S was found to be a potent growth inhibitor of M. tuberculosis (MIC 99 ϭ 12.5 g/ml), although it differs only in one stereogenic center located in the alkenyl side chain from mycobactin T, the endogenously produced mycobactin of M. tuberculosis (146). Testing of further synthetic mycobactin analogues as antitubercular agents revealed one compound, which carried a Boc-protecting group, with an MIC 98 of 0.2 g/ml (346). The molecular mechanism of the inhibitory effect of heterologous mycobactins in mycobacteria awaits further characterization, and it can be assumed that the mycobactin analogues interfere with the uptake of iron delivered by endogenously derived mycobactins.…”

Cinnamic Derivatives in Tuberculosis

“…is challenging for several reasons. The complexity of the mycobactin architecture itself poses a daunting synthetic challenge, which hampers the generation of conjugates (Xu & Miller, 1998). Further, the iron transport mechanism involves an "iron-handoff" between two siderophore families, the exochelins and the mycobactins.…”