Ten-step asymmetric total syntheses of potent antibiotics anthracimycin and anthracimycin B.
Chem Sci
; 13(43): 12776-12781, 2022 Nov 09.
Article
em En
| MEDLINE
| ID: mdl-36519065
ABSTRACT
The increase in antibiotic resistance calls for the development of novel antibiotics with new molecular structures and new modes of action. However, in the past few decades only a few novel antibiotics have been discovered and progressed into clinically used drugs. The discovery of a potent anthracimycin antibiotic represents a major advance in the field of antibiotics. Anthracimycin is a structurally novel macrolide natural product with an excellent biological activity profile (i) potent in vitro antibacterial activity (MIC 0.03-1.0 µg mL-1) against many methicillin-resistant Staphylococcus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis; (ii) low toxicity to human cells (IC50 > 30 µM); (iii) a novel mechanism of action (inhibiting DNA/RNA synthesis). While the first total synthesis of anthracimycin was elegantly accomplished by Brimble et al. with 20 steps, we report a 10-step asymmetric total synthesis of anthracimycin and anthracimycin B (first total synthesis). Our convergent strategy features (i) one-pot sequential Mukaiyama vinylogous aldol/intramolecular Diels-Alder reaction to construct trans-decalin with high yield and excellent endo/exo selectivity and (ii) Z-selective ring-closing metathesis to forge the 14-membered ring. In vitro antibacterial evaluation suggested that our synthetic samples exhibited similar antibacterial potency to the naturally occurring anthracimycins against Gram-positive strains. Our short and reliable synthetic route provides a supply of anthracimycins for further in-depth studies and allows medicinal chemists to prepare a library of analogues for establishing structure-activity relationships.
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Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Idioma:
En
Revista:
Chem Sci
Ano de publicação:
2022
Tipo de documento:
Article