Melicopteline A–E, Unusual Cyclopeptide Alkaloids with Antiviral Activity against Influenza A Virus from Melicope pteleifolia

Abstract

In the search for antiviral cyclopeptides against influenza A virus, five unprecedented Caryophyllaceae-type cyclopeptides (1–5) were isolated from the leaves of Melicope pteleifolia. Their chemical structures and absolute configurations were unambiguously determined by means of advanced Marfey’s analysis and comprehensive spectroscopic analyses including two-dimensional nuclear magnetic resonance and MS/MS fragmentation. Interestingly, compounds 3–5 contain an unusual heterocycle, a 3a-hydroxypyrroloindole moiety, which was biosynthetically formed by a nucleophilic cyclization from the least abundant amino acid, tryptophan, precursor and has aroused a great interest in the aspect of chemical diversity and biological activity. All isolates (1–5) were evaluated for their protective effects against influenza A viruses H1N1 and H9N2 in MDCK cells. All isolated cyclopeptides exhibited strong anti-influenza activity, especially against H1N1. Compound 3 showed the most potent CPE inhibition effect, which was stronger than that of the positive control ribavirin against H1N1, with an EC50 (μM) of 2.57 ± 0.45 along with higher selectivity.

Synthesis and anti‐hepatocellular carcinoma activity in vitro of cyclic peptide GG‐8‐6 analogues

“…Natural products provide various chemical structures for the development of drug discovery. Among them, natural resource cyclic peptides belong to a particular class of compounds that display broad activities ranging from antiviral to antibacterial and anticancer applications [2–7]. Compared with linear peptides, cyclopeptides are more stable because of the absence of both free amino and carboxyl groups in their structures.…”

Total Synthesis of Melicoptelines C–E: Antiviral Cyclopeptides Containing a Hexahydropyrrolo[2,3-b]indole Moiety

“…2 Very recently, the Oh group, one of our research collaborators, isolated new cyclopeptides melicoptelines A−E from the leaves of Melicope pteleifolia, which has been traditionally used in China and Vietnam for the treatment of cold and flu accompanying high fever and pain. 3 They evaluated the anti-influenza activity of the isolated melicoptelines and found that the activity of melicoptelines C−E containing a hexahydropyrrolo[2, 3-b]indole (HPI) moiety is stronger than those of other isolated melicoptelines (Figure 1). We assumed that this HPI moiety can act as an important pharmacophore and thus designed a total synthesis of melicoptelines C−E for medicinal studies of anti-influenza drugs.…”

“…The structures of synthetic melicoptelines C−E were confirmed by spectral analysis, and these compounds were found to be identical to the natural compounds (page S-30 of the Supporting Information). 3 Furthermore, diastereomeric melicopteline 4 was also synthesized through the same procedure by applying anti-cis HPI 9b instead of syn-cis HPI 9a (Scheme 5).…”

“…Therefore, these peptide compounds are attractive and promising pharmaceuticals . Very recently, the Oh group, one of our research collaborators, isolated new cyclopeptides melicoptelines A–E from the leaves of Melicope pteleifolia , which has been traditionally used in China and Vietnam for the treatment of cold and flu accompanying high fever and pain . They evaluated the anti-influenza activity of the isolated melicoptelines and found that the activity of melicoptelines C–E containing a hexahydropyrrolo­[2,3- b ]­indole (HPI) moiety is stronger than those of other isolated melicoptelines (Figure ).…”

Hot off the Press

“…Melicopteline C 5 , from leaves of Melicope pteleifolia , is a cyclic hexapeptide with an unusual pyrroloindole ring system and shows potent antiviral activity. 5 A pathway for the formation of the pyrroloindole ring system from a tryptophan residue has been proposed.…”