Antiproliferative Bistramides from Trididemnum cyclops from Madagascar

Abstract

Bioassay-guided fractionation of a marine extract from Trididemnum cyclops afforded the new lipopeptide 39-oxobistramide K (1) and the known bistramides A (2) and D (3). Structure elucidation of 1 was carried out by analysis of one and two-dimensional NMR spectroscopy and HRMS data. Bistramides have been reported to exhibit antiproliferative activity in the nanomolar range against a number of tumor cell lines in vitro and in vivo. The isolate 1 was tested for antiproliferative activity against the A2780 cell line, and exhibited an IC 50 value of 0.34 µM.In our continuing search for biologically active natural products from Madagascar as part of an International Cooperative Biodiversity Group (ICBG) program, 1 an extract was obtained from the tunicate Trididemnum cyclops Michaelsen 1921 (Didemnidae). The marine invertebrate Trididemnum has been the source of a number of potently bioactive compounds, of which the most frequently reported in the literature and subsequently found to be the most bioactive are a class of cyclic depsipeptides known as didemnins. Rinehart et al. reported the first occurrence of these amino acid macrocycles from Trididemnum solidum. 2 One of the isolates was didemnin B, the first marine-derived compound to enter Phase I and Phase II clinical trials by the National Cancer Institute as a potential antitumor agent.In the current study, an extract of T. cyclops showed significant antiproliferative activity against the A2780 ovarian cancer cell line, and it was thus selected for study. Fractionation yielded one new and two known bistramides. Bistramides are a class of polyether amides with methylated tetrahydropyran and spiroketal subunits. The first of its kind, bistramide A (2), was discovered in 1988 by Gouiffes et al. from the ascidian Lissoclinum bistratum, also of the family Didemnidae. 3 The bistramides have been shown to display diverse bioactivities, including immunomodulating and weak antimalarial activity, 4,5 but their most notable trait is their antitumor properties. Statsuk et al. reported that actin, a protein essential for cellular motility and division, is the primary cellular receptor of bistramide A. 6 In a series of cell-based and in vitro studies in conjunction with affinity-based protein isolation, it was determined that * To whom correspondence should be addressed. Tel: (540) 231-6570. Fax: (540) 231-3255. dkingston@vt.edu. § These authors contributed equally to this work. Present addresses: B.T.M., Scripps Institution of Oceanography, University of California, San Diego, La Jolla CA 92093-0204. S.C., Harvard Medical School, Biological Chemistry and Molecular Pharmacology, 240 Longwood Avenue, Boston MA 02115-5701.Supporting Information Available: Spectroscopic data, consisting of 1 H NMR spectroscopic data of bistramides A (2) and D (3), 1 H NMR, ROESY, COSY, HSQC, HMBC, and CD spectra of 39-oxobistramide K (1), 1 H NMR, 13 C NMR, COSY, HMBC, and CD spectra of bistramide A (2), the 1 H NMR spectrum of bistramide D (3), and a photograph of a sample of Trididemn...

Spiroketals: Toward the synthesis of 39-oxobistramide K

“…39-Oxobistramide K was extracted from the tunicate Trididemnum cyclops Michaelsen in 1921 [2] in conjunction with two other bistramides, bistramides A and D, which were previously isolated in 1988 by Gouiffès et al from the ascidian Lissoclinum bistratum [19] and belong to the Didemnidae family (Scheme 3) [20].…”

“…39-Oxobistramide K is a new lipopeptide, and its structure elucidation was carried out by analysis of one-and two-dimensional NMR spectroscopy and high-resolution mass spectrometry (HRMS) data [2]. We have to point out that the stereogenic center at C4 was not elucidated.…”

“…We have to point out that the stereogenic center at C4 was not elucidated. 39-Oxobistramide K has been reported to have antiproliferative activity against the A2780 cell line and exhibited an IC 50 value of 0.34 μM [2]. Owing to its biological properties and its challenging molecular architecture, we decided to embark on the synthesis of 39-oxobistramide K according to a convergent approach and by utilizing the spiroketalization of an ω-unsaturated lactol induced by FeCl 3 , as the key step (Scheme 2, eq.…”

“…For our part, we were interested in the synthesis of spiroketals from unsaturated lactols by utilizing FeCl 3 and applying this method to the synthesis of 39-oxobistramide K, an antiproliferative agent [2].…”

The Medicinal Value of Biodiversity: New Hits to Fight Cancer

“…Recently, its enantioselective synthesis was described (Fortner et al, 2010). Bistramine A is a polyketide derivative isolated from ascidian such as Lissoclinum bistratum, but it is also found in a tunicate Trididemnum cyclops (Murphy et al, 2009). This compound disrupted the actin cytoskeleton, depolymerized F-actin in vitro and bound directly to monomeric G-actin (Rizvi et al, 2010).…”