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Article

Sponge-Derived Fijianolide Polyketide Class: Further Evaluation of Their Structural and Cytotoxicity Properties

Supporting Info

Tyler A. Johnson,^† Karen Tenney,^† Robert H. Cichewicz,^† Brandon I. Morinaka,^† Kimberly N. White,^† Taro Amagata,^† Balanehru Subramanian,^‡ Joseph Media,^‡ Susan L. Mooberry,^§ Frederick A. Valeriote,^‡ and Phillip Crews*^†

Department of Chemistry and Biochemistry and Institute for Marine Sciences, University of California, Santa Cruz, California 95064, Josephine Ford Cancer Center, Henry Ford Health System, Detroit, Michigan 48202, and Southwest Foundation for Biomedical Research, San Antonio, Texas 78245

J. Med. Chem., 2007, 50 (16), pp 3795–3803

DOI: 10.1021/jm070410z

Publication Date (Web): July 10, 2007

†

University of California, Santa Cruz.

‡

Josephine Ford Cancer Center.

Southwest Foundation for Biomedical Research.

To whom correspondence should be addressed. Tel.: 831-459-2603. Fax: 831-459-2935. E-mail: phil@chemistry.ucsc.edu.

Abstract

The sponge-derived polyketide macrolides fijianolides A (1) and B (2), isolaulimalide and laulimalide, have taxol-like microtubule-stabilizing activity, and the latter exhibits potent cytotoxicity. Insight on the biogeographical and phenotypic variations of Cacospongia mycofijiensis is presented that will enable a future study of the biosynthetic pathway that produces the fijianolides. In addition to fijianolides A and B, six new fijianolides, D−I (7−12), were isolated, each with modifications to the C-20 side chain of the macrolide ring. Compounds 7−12 exhibited a range of in vitro activities against HCT-116 and MDA-MB-435 cell lines. Fijianolides 8 and 10 were shown to disrupt interphase and mitotic division, but were less potent than 2. An in vivo evaluation of 2 using tumor-bearing severe combined immuno-deficiency mice demonstrated significant inhibition of growth in HCT-116 tumors over 28 days.