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. 2015 Jan 1;23(1):126-31.
doi: 10.1016/j.bmc.2014.11.021. Epub 2014 Nov 20.

Bioactive metabolites from Chaetomium aureum: structure elucidation and inhibition of the Hsp90 machine chaperoning activity

Fatima Zahra Kabbaj  1 , Su Lu  2 , My El Abbés Faouzi  3 , Bouchra Meddah  3 , Peter Proksch  4 , Yahya Cherrah  3 , Hans-Josef Altenbach  5 , Amal H Aly  4 , Ahmed Chadli  6 , Abdessamad Debbab  7
Affiliations

Bioactive metabolites from Chaetomium aureum: structure elucidation and inhibition of the Hsp90 machine chaperoning activity

Fatima Zahra Kabbaj et al. Bioorg Med Chem. .

Abstract

Chemical investigation of the EtOAc extract of the fungus Chaetomium aureum, an endophyte of the Moroccan medicinal plant Thymelaea lythroides, afforded one new resorcinol derivative named chaetorcinol, together with five known metabolites. The structures of the isolated compounds were determined on the basis of one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry as well as by comparison with the literature. All compounds were tested for their activity towards the Hsp90 chaperoning machine in vitro using the progesterone receptor (PR) and rabbit reticulocyte lysate (RRL). Among the isolated compounds, only sclerotiorin efficiently inhibited the Hsp90 machine chaperoning activity. However, sclerotiorin showed no cytotoxic effect on breast cancer Hs578T, MDA-MB-231 and prostate cancer LNCaP cell lines. Interestingly, deacetylation of sclerotiorin increased its cytotoxicity toward the tested cell lines over a period of 48 h.

Keywords: Bioactive metabolites; Chaetomium aureum; Cytotoxicity; Hsp90; Structure elucidation.

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Figures

Chart 1
Chart 1
Structures of the isolated compounds 1-7.
Figure 1
Figure 1
Key ROESY (↔) and HMBC correlations (→) of 1.
Figure 2
Figure 2
Effect of 1-6 on the Hsp90 chaperoning machine in vitro. A. PR hormone binding activity was reconstituted using rabbit reticulocyte lysate without (RL) or with the metabolites 1-6. 17-AAG is used as a positive control. B. Samples from (A) were used for analysis of protein complexes by SDS-PAGE and Coomassie blue staining. PR22 indicates the PR antibody incubated with RRL . PR indicates the PR alone with no RRL.
Figure 3
Figure 3
Comparison of 2 and 6. A. Effect increasing concentration of 2 and 6 on PR hormone binding activity. B. Effect of 2 and 6 on PR protein complexes. Molecular chaperones are indicated on the right. HC represents the heavy chains of the PR antibody PR22.
Figure 4
Figure 4
A. Comparison of the effect of 2 and 6 on cell survival of the breast cancer cell line Hs578Tusing MTS assay. B. 6 inhibits the growth of breast cancer cell line MDA-MB-231 and prostate cancer cell line LNCaP. C. Western blot analysis comparing the effect of 2 and 6 on the expression of Hs70, Hsp40 and GR. b-actin is used as a loading control.
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