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Chapter 1 The total synthesis of luzopeptins

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DOI: 10.1016/s1874-6004(05)80024-3
Disciplines
  • Chemistry
  • Medicine

Abstract

Publisher Summary Since their isolation, luzopeptins have attracted interest in the biomedical arena, but their rarity and chemical sensitivity have precluded any sort of chemical modification that may be required for a thorough medicinal chemistry study. A viable synthesis was needed to address these issues. Thus, the quest for total synthesis of luzopeptins began, which has been documented in this chapter. Inouye confirmed the activity of luzopeptin C against HIV-RT (RT-reverse transcriptase) and disclosed that luzopeptin C suppresses HIV replication in infected MT-4 cells at non-cytopathic concentrations. Luzopeptin C must, thus, be selective for RT vis-a-vis human DNA polymerases. The chapter discusses the mechanism of action of luzopeptins and the minimal structural requisites for anti-HIV activity and reviews answers to whether luzopeptins A and luzopeptins C serve as anti-HIV drugs and, if so, the way could they be modified to further enhance potency and selectivity. Together with quinoxapeptins, sandramycin, and related natural products, luzopeptins form what may be referred to as the “peptin family of natural products.” Peptins display a dimeric peptide scaffold of C2-like symmetry that supports a pair of heteroaroyl segments. These appear to be intimately involved in the expression of bioactivity. The synthesis of luzopeptins is fraught with extreme difficulties. At some point, a linear dimer of pentadepsipeptide must undergo cyclization. However, the efficiency of the cyclization of linear peptides is known to be sequence-dependent and sensitive even to minor structural changes in the substrate, including the nature of protecting groups.

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