Bioorganic & Medicinal Chemistry 2015-08-01

Hedgehog inhibitors from Artocarpus communis and Hyptis suaveolens.

Midori A Arai, Kyoko Uchida, Samir K Sadhu, Firoj Ahmed, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

Index: Bioorg. Med. Chem. 23 , 4150-4, (2015)

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Abstract

The hedgehog (Hh) signaling pathway plays crucial roles in cell maintenance and proliferation during embryonic development. Naturally occurring Hh inhibitors were isolated from Artocarpus communis and Hyptis suaveolens using our previously constructed cell-based assay system. Bioactivity guided fractionation led to the isolation of 15 compounds, including seven new compounds (4, 5, 6, 7, and 9-11). The isolated compounds showed cytotoxicity against a cancer cell line (PANC1) in which Hh signaling was abnormally activated. Several compounds (12-14; GLI1 transcriptional inhibition IC50=7.6, 4.7, and 4.0 μM, respectively) inhibited Hh related protein (BCL2) expression. Moreover, compounds 1, 12, and 13 disrupted GLI1 and DNA complex formation.Copyright © 2015 Elsevier Ltd. All rights reserved.