当前位置：
X-MOL 学术
›
ACS Cent. Sci.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis.
ACS Central Science ( IF 12.7 ) Pub Date : 2020-05-04 , DOI: 10.1021/acscentsci.0c00122 Fan Wu 1 , Jing Zhang 1 , Fuhang Song 2 , Sanshan Wang 1 , Hui Guo 2 , Qi Wei 2 , Huanqin Dai 2 , Xiangyin Chen 3 , Xuekui Xia 3, 4 , Xueting Liu 3 , Lixin Zhang 2, 3, 4 , Jin-Quan Yu 5 , Xiaoguang Lei 1
ACS Central Science ( IF 12.7 ) Pub Date : 2020-05-04 , DOI: 10.1021/acscentsci.0c00122 Fan Wu 1 , Jing Zhang 1 , Fuhang Song 2 , Sanshan Wang 1 , Hui Guo 2 , Qi Wei 2 , Huanqin Dai 2 , Xiangyin Chen 3 , Xuekui Xia 3, 4 , Xueting Liu 3 , Lixin Zhang 2, 3, 4 , Jin-Quan Yu 5 , Xiaoguang Lei 1
Affiliation
|
Tuberculosis (TB) is a life-threatening disease resulting in an estimated 10 million new infections and 1.8 million deaths annually, primarily in underdeveloped countries. The economic burden of TB has been estimated as approximately 12 billion USD annually in direct and indirect costs. Additionally, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB strains resulting in about 250 000 deaths annually are now widespread, increasing pressure on the identification of new anti-TB agents that operate by a novel mechanism of action. Chrysomycin A is a rare C-aryl glycoside first discovered over 60 years ago. In a recent high-throughput screen, we found that chrysomycin A has potent anti-TB activity, with minimum inhibitory concentration (MIC) = 0.4 μg/mL against MDR-TB strains. However, chrysomycin A is obtained in low yields from fermentation of Streptomyces, and the mechanism of action of this compound is unknown. To facilitate the mechanism of action and preclinical studies of chrysomycin A, we developed a 10-step, scalable synthesis of the isolate and its two natural congeners polycarcin V and gilvocarcin V. The synthetic sequence was enabled by the implementation of two sequential C–H functionalization steps as well as a late-stage C-glycosylation. In addition, >10 g of the advanced synthetic intermediate has been prepared, which greatly facilitated the synthesis of 33 new analogues to date. The structure–activity relationship was subsequently delineated, leading to the identification of derivatives with superior potency against MDR-TB (MIC = 0.08 μg/mL). The more potent derivatives contained a modified carbohydrate residue which suggests that further optimization is additionally possible. The chemistry we report here establishes a platform for the development of a novel class of anti-TB agents active against drug-resistant pathogens.
中文翻译：
用于治疗多重耐药结核病的红霉素 A 衍生物。
结核病 (TB) 是一种危及生命的疾病，估计每年导致 1000 万人新感染和 180 万人死亡，主要发生在不发达国家。据估计，每年结核病造成的直接和间接经济负担约为 120 亿美元。此外，耐多药 (MDR) 和极端耐药 (XTR) 结核菌菌株现在普遍存在，每年导致约 25 万人死亡，这增加了识别通过新机制发挥作用的新型抗结核药物的压力。行动。 Chrysomycin A 是一种罕见的 C-芳基糖苷，于 60 多年前首次发现。在最近的高通量筛选中，我们发现chrysomycin A具有有效的抗结核活性，对耐多药结核菌株的最低抑制浓度（MIC）= 0.4 μg/mL。然而，从链霉菌发酵中获得的红霉素A的收率很低，并且该化合物的作用机制尚不清楚。为了促进红霉素 A 的作用机制和临床前研究，我们开发了该分离物及其两种天然同系物 Polycarcin V 和 gilvocacin V 的 10 步可扩展合成方法。合成序列是通过实施两个连续的 C-H 实现的。功能化步骤以及后期 C-糖基化。此外，还制备了>10 g的高级合成中间体，极大地促进了迄今为止33个新类似物的合成。随后描述了结构-活性关系，从而鉴定出具有优异抗 MDR-TB 效力的衍生物（MIC = 0.08 μg/mL）。更有效的衍生物含有修饰的碳水化合物残基，这表明进一步优化也是可能的。 我们在此报告的化学反应为开发一类新型抗结核药物建立了一个平台，该药物可有效对抗耐药病原体。
更新日期：2020-06-24
中文翻译：
用于治疗多重耐药结核病的红霉素 A 衍生物。
结核病 (TB) 是一种危及生命的疾病，估计每年导致 1000 万人新感染和 180 万人死亡，主要发生在不发达国家。据估计，每年结核病造成的直接和间接经济负担约为 120 亿美元。此外，耐多药 (MDR) 和极端耐药 (XTR) 结核菌菌株现在普遍存在，每年导致约 25 万人死亡，这增加了识别通过新机制发挥作用的新型抗结核药物的压力。行动。 Chrysomycin A 是一种罕见的 C-芳基糖苷，于 60 多年前首次发现。在最近的高通量筛选中，我们发现chrysomycin A具有有效的抗结核活性，对耐多药结核菌株的最低抑制浓度（MIC）= 0.4 μg/mL。然而，从链霉菌发酵中获得的红霉素A的收率很低，并且该化合物的作用机制尚不清楚。为了促进红霉素 A 的作用机制和临床前研究，我们开发了该分离物及其两种天然同系物 Polycarcin V 和 gilvocacin V 的 10 步可扩展合成方法。合成序列是通过实施两个连续的 C-H 实现的。功能化步骤以及后期 C-糖基化。此外，还制备了>10 g的高级合成中间体，极大地促进了迄今为止33个新类似物的合成。随后描述了结构-活性关系，从而鉴定出具有优异抗 MDR-TB 效力的衍生物（MIC = 0.08 μg/mL）。更有效的衍生物含有修饰的碳水化合物残基，这表明进一步优化也是可能的。 我们在此报告的化学反应为开发一类新型抗结核药物建立了一个平台，该药物可有效对抗耐药病原体。
京公网安备 11010802027423号