Background: Heat shock protein 90 is a molecular chaperone required for the stability and
function of several client proteins that promote cancer cell growth and/or survival. Discovery of Hsp90
inhibitors has emerged as an attractive target of research in cancer therapeutics. Natural products like
geldanamycin and radicicol are established Hsp90 inhibitors, but face limitations with toxicity and inactivity,
by in vivo studies respectively. However, they lay the logical starting point for the design of
novel synthetic or semi-synthetic congeners as Hsp90 inhibitors.
Objective: In this article, the structure based drug design of substituted 2-aryl/heteroarylidene-6-
hydroxybenzofuran-3(2H)-one analogues to optimize and mimic the pharmacophoric interactions of
the valid Hsp90 inhibitor radicicolis focused.
Method: In silico docking study was performed by Surflex dock-Geom (SYBYL- X 1.2 drug discovery
suite) and the designed ligands were chemically synthesized by conventional method using resorcinol
and chlororesorcinol as starting materials. Two dimensional chemical similarity search was carried
out to identify the chemical space of ‘SY' series in comparison with reported Hsp90 inhibitors.
The in vitro cell proliferation assay (resazurin reduction method) and proteomic investigation
(DARTS) was carried out on whole cell lysate to evaluate anticancer activity.
Results: The chemical structures of all the synthesized compounds were confirmed by IR, 1H-NMR and
Mass spectral analysis. The results of chemical similarity search show that SY series fit it in the chemical
space defined by existing Hsp90 inhibitors. In vitro cell proliferation assay, against human melanoma and
breast cancer cell lines, identified ‘SY3' as the promising anticancer agent amongst the series.
Conclusion: Docking studies, 2D chemical similarity search, resazurin reduction assay and qualitative
proteomic analysis identify ‘SY3’as a promising Hsp90 inhibitor amongst the series.