Department of Chemistry
Total Synthesis of Potent Antibiotic Anthracimycins
The rise of antibiotic resistance calls for the development of novel antibiotics with new molecular structure and new mode of action. However, in the past decades only a few novel antibiotics were discovered and progressed into clinically used drugs. The discovery of 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) against many methicillin-resistant Staphyloccoccus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis; ii) low toxicity to human cells (IC50 >30 μM); iii) novel mechanism of action (inhibiting DNA/RNA synthesis). Herein, 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 the 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 our synthetic samples exhibited similar antibacterial potency as 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 relationship.
Prof. Tong and his co-workers in his lab at HKUST
Total synthesis and Antibacterial Activity of Anthracimycin (Ant) and Anthracimycin B (Ant B) (MIC μg/mL)
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- Associate Professor, Department of Chemistry
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