Four novel bis-(naphtho-γ-pyrones) isolated from Fusarium species as inhibitors of HIV-1 integrase

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Abstract

Integration of viral DNA into host cell DNA is an essential step in retroviral (HIV-1) replication and is catalyzed by HIV-1 integrase. HIV-1 integrase is a novel therapeutic target and is the focus of efforts to identify effective inhibitors that will prevent/or cure HIV infections. Four novel naphtho-γ-pyrones, belonging to the chaetochromin and ustilaginoidin family, were discovered as inhibitors of HIV-1 integrase from the screening of fungal extracts using a recombinant in vitro assay. These compounds inhibit both the coupled and strand transfer activity of HIV-1 integrase with IC50 values of 1–3 and 4–12 μM, respectively. The discovery, structure elucidation, chemical modification and the structure–activity relationship of these compounds are described.

Four novel naphtho-γ-pyrones and derivatives with coupled and strand transfer activity of HIV-1 integrase with IC50 values ranging 1–12 μM have been described.

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Producing Organism, Fermentation and Isolation

The culture (MF6252, ATCC74396) that produced these compounds was isolated from leaf litter collected under Podocarpus dacryoides in Te Anau, New Zealand. It was identified as a Fusarium sp. and was grown in CYS80 media.7 A 1.2-L fermentation broth was extracted with methyl ethyl ketone and the extract was chromatographed on Sephadex LH-20 in MeOH yielding three consecutive fractions containing the active components. The first and third fractions were chromatographed by RPHPLC (Zorbax RX C-8,

Structure elucidation

HREIMS analysis of 1 and 2 indicated that they were isomeric and gave a parent ion at m/z 546 suggesting a molecular formula C30H26O10. The 13C NMR spectra revealed the presence of 30 carbons and supported the formula. The formula search of these compounds in the Chapman and Hall database provided chaetochromins A (5),9 B (6)9 and ustilaginoidin D (7)10 as hits which was further narrowed to the unsymmetrical dimer chaetochromin B by a 13C NMR similarity search in the SIMSER database.11

Acknowledgements

The authors thank Delia Valentino for fermentation studies.

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