Cytotoxic Clerodane Diterpenoids and Their Hydrolysis Products from <em>Casearia nigrescens</em> from the Rainforest of Madagascar

Russell Williams

Andrew Norris

James Miller

Chris Birkinshaw

Fidy Ratovoson

Rabodo Andriantsiferana

Vincent Rasamison

David Kingston

^{Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0212}

^{Missouri Botanical Garden, P.O. Box 299, St. Louis, Missouri 63166-0299}

^{Missouri Botanical Garden, B.P 3391, Antananarivo 101, Madagascar}

^{Centre National d’Application des Recherches Pharmaceutiques, B.P. 702, Antananarivo 101, Madagascar}

^{To whom correspondence should be addressed. Tel: (540) 231-6570. Fax: (540) 231-7702. E-mail:}ude.tv@notsgnikd

Bioassay-guided fractionation of the cytotoxic leaf and flower extract of Casearia nigrescens led to the isolation of four new clerodane diterpenoids, designated caseanigrescens A–D (1–4). These compounds were subject to hydrolysis to dialdehydes when stored in CDCl₃. The structures of compounds 1–4 were determined using 1D and 2D NMR spectroscopy. All four compounds showed moderate cytotoxicity to the A2780 human ovarian cancer cell line, with an IC₅₀ range of 0.83–1.4 µM.

In our continuing search for bioactive molecules from the rainforests of Madagascar as part of an International Cooperative Biodiversity Group (ICBG) program,² an extract of the leaves and flowers of Casearia nigrescens Tul. (Flacourtiaceae) showed moderate cytotoxicity against the A2780 human ovarian cancer cell line. This extract was selected for fractionation based on its cytotoxicity and the lack of phytochemical data for this species. The crude extract was purified by liquid–liquid partition, reversed phase chromatography, and reversed phase HPLC to yield the four new clerodane diterpenoids 1–4, designated caseanigrescens A–D. These compounds were subject to hydrolysis to dialdehydes when stored in CDCl₃.

The genus Casearia is a member of the Saliciaceae. It consists of about 180 species and occurs throughout the tropics. Five species are found in Madagascar.³4 The Flacourtiaceae family, and Casearia in particular, are well known for the production of clerodane diterpenoids.⁵8 Such compounds have been reported to possess a wide range of biological activities including cytotoxic, antimalarial, antimycobacterial, DNA-damaging, trypanocidal, immunosuppressive, antifungal, and apoptosis inducing activity.⁵7915C. nigrescens is known locally as Hazondrano.

Footnotes

Supporting Information Available:^{H and}^{C NMR spectra for compounds}1–4 and 7; ^{H NMR spectrum of compound}6. This material is available free of charge via the Internet at http://pubs.acs.org.

Footnotes

References and Notes

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