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Article

Lipophilic 2,5-Disubstituted Pyrroles from the Marine Sponge Mycale sp. Inhibit Mitochondrial Respiration and HIF-1 Activation

Supporting Info

Shui-Chun Mao^†, Yang Liu^†, J. Brian Morgan^†, Mika B. Jekabsons^‡, Yu-Dong Zhou*^† and Dale G. Nagle*^†^§

Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, and Department of Biology, University of Mississippi, University, Mississippi 38677

J. Nat. Prod., 2009, 72 (11), pp 1927–1936

DOI: 10.1021/np900444m

Publication Date (Web): October 21, 2009

* Corresponding authors. (Y.-D.Z.) Tel: (662) 915-7026. Fax: (662) 915-6975. E-mail: ydzhou@olemiss.edu. (D.G.N.) Tel: (662) 915-7026. Fax: (662) 915-6975. E-mail: dnagle@olemiss.edu., †

Department of Pharmacognosy.

, ‡

Department of Biology.

, §

Research Institute of Pharmaceutical Sciences.

Abstract

The lipid extract of the marine sponge Mycale sp. inhibited the activation of hypoxia-inducible factor-1 (HIF-1) in a human breast tumor T47D cell-based reporter assay. Bioassay-guided isolation and structure elucidation yielded 18 new lipophilic 2,5-disubstituted pyrroles and eight structurally related known compounds. The active compounds inhibited hypoxia-induced HIF activation with moderate potency (IC₅₀ values <10 μM). Mechanistic studies revealed that the active compounds suppressed mitochondrial respiration by blocking NADH-ubiquinone oxidoreductase (complex I) at concentrations that inhibited HIF-1 activation. Under hypoxic conditions, reactive oxygen species produced by mitochondrial complex III are believed to act as a signal of cellular hypoxia that leads to HIF-1α protein induction and activation. By inhibiting electron transport (or delivery) to complex III under hypoxic conditions, lipophilic Mycale pyrroles appear to disrupt mitochondrial ROS-regulated HIF-1 signaling.

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