Analogues of Chrysomycin A as Leads for Drug-Resistant Tuberculosis

Tuberculosis (TB) remains a major cause of death globally, primarily in underdeveloped countries, and imposes approximately 12 billion USD annually in economic burdens to society. Furthermore, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB are widespread illnesses that cause up to 250,000 deaths annually, thus emphasizing the need for drugs with new mechanisms of action. Recently, the natural product chrysomycin A was identified as having potent anti-TB activity in a high-throughput screen (MIC = 0.4 µg/mL against MDR-TB). Chrysomycin A is a rare C-aryl glycoside whose yields via fermentation from its natural source are insufferably low. To provide sufficient materials for biological testing, the group of Xiaoguang Lei devised a total synthesis route to chrysomycin A (1), its natural congeners polycarcin V (8) and gilvocarcin V (10, Figure 1), and 33 new analogues. 

The preparation of a late-stage intermediate that is amenable to diversification is shown in Figure 2A. Notably, modern synthetic strategies, including a regioselective Ir catalyzed C–H borylation and Ag catalyzed C–H oxygenation, were critical to achieving a step economical synthesis. Glycosyl donors (23, Figure 2B) were prepared according to literature procedures, with some modifications, in 10 steps. Linking the carbohydrate fragment with the aromatic system was a challenging key step that required considerable optimization (Figure 3), including the judicious use of the appropriate amount of activated 4 Å MS (20% w/w) to achieve acceptable yields of product with the correct regioselectivity on the aromatic system (i.e., C4 vs. C2) as well as anomeric selectivity on the glycosyl system (i.e., α vs. β). It should be emphasized that one of the most important aspects of this work was the synthesis of carbohydrate-modified analogues. Similar to complex molecule synthesis, multi-step carbohydrate synthesis is generally challenging and limited to research programs with significant expertise and training in this area. This is also reflected by the tedious optimization of the key C-glycosidation step. This same route was successfully

diverged to access gilvocarcin V and polycarcin V in a manner more efficient than previously reported total syntheses. Finally, the authors synthesized a library of analogues (Table 2), and were able to identify some with enhanced potency [e.g., (+)-64, MIC = 0.08 µg/mL against MDR-TB]. In summary, the authors have developed a sustainable process for producing new potential drug leads for TB, and have shown proof-of-principle for justifying carbohydrate-modified analogues of chrysomycin A.

Reference:

Wu, F.; Zhang, J.; Song, F.; Wang, S.; Guo, H.; Wei, Q.; Dai, H.; Chen, X.; Xia, X.; Liu, X.; Zhang, L.; Yu, J.-Q.; Lei, X. ACS Cent. Sci. 2020, doi: 10.1021/acscentsci.0c00122.