Bengamides Revisited:  New Structures and Antitumor Studies

Abstract

The structural chemistry and biological activity of the bengamide class of compounds have been further characterized. Extracts prepared from recollected Jaspis cf. coriacea from five sites in Fiji were pooled. Six new bengamides, M (7b), N (8a), O (8b), P (9a), Q (9b), and R (10), were identified, accompanied by the known bengamides A (1a), B (1b), E (3a), F (3b), Y (5), Z (6), L (7a), G (11a), H (11b), and I (12). The structures of the new compounds were determined from spectroscopic data, and some were additionally confirmed by semisynthesis. Cytotoxicity screening data were obtained from the NCI-DTP 60 cell screen for bengamides A, B, and P. Bengamides A and B were more potent than bengamide P, with average IC(50) values of 0.046, 0.011, and 2.70 FM, respectively. The in vitro antitumor activity against MDA-MB-435 human mammary carcinoma was also determined for natural bengamides A, B, E, F, P, M, O, and Z and for synthetic samples of B and O. The best activity was observed for the natural bengamides A (IC(50) = 1 nM) and O (IC(50) = 0.3 nM).

Proteomics-based Target Identification

“…However, despite the lack of specificity in vitro, tumor-specific activity was seen with bengamides in vivo, as demonstrated by the striking antitumor activity in xenograft models at well tolerated doses (3). In additional studies comparing more frequent dosing, LAF389 has been observed to result in tumor regression, 2 an effect more pronounced than the in vivo responses reported with a potent fumagillin analogue, TNP-470, which gave at most cytostatic activity in human tumor xenograft models (27).…”

“…Confirmation of the assignment of the N-terminal sequences was performed by nano-ESMS/MS sequencing. Direct selection of the triply charged parent ion at m/z 421.22 from the Lys-C digest of the induced 14-3-3␥ isoform and subsequent fragmentation produced sufficient y and b type fragment ions to identify unambiguously the sequence of the peptide as M(oxi)-VDREQLVQK (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). A similar analysis of the aminoterminal peptide of the tryptic digest of the constitutive 14-3-3␥ confirmed the complete sequence as acetyl-VDREQLVQK (2-10) (data not shown).…”

“…Bengamide B is one of the most potent members of the family; it causes growth inhibition in vitro at low nM concentrations on all human tumor cell lines tested (2). In vivo, it significantly inhibits growth of MDA-MB435 human breast cancer xenografts at well tolerated doses (3).…”

“…In vivo, it significantly inhibits growth of MDA-MB435 human breast cancer xenografts at well tolerated doses (3). In vitro studies of bengamide B suggested its activity might be due to inhibition of a novel target, because its pattern of activity in the NCI 60 cell line screening panel was unique compared with that of other chemotherapeutic agents (2). Although bengamide B was a potent lead structure, its limited availability from natural sources, the complexity of its synthesis, and its relatively poor solubility prevented further development of the compound as a therapeutic agent.…”

New Glycerides from a Two-Sponge Association ofJaspissp. andPoecillastrasp.

“…Sponges of the genus Jaspis are reported to contain many biologically active molecules, which include macrolides [jaspisamides (Kobayashi et al, 1993)], cyclic peptides [jaspamides (Gala et al, 2007) or jasplakinolide (Crews et al, 1986)], amino acid derivatives [bengamides (Thale et al, 2001) and bengazoles (Groweiss et al, 1999)], and triterpenes (Tang et al, 2006). Similarly, macrolide lactams [poecillastrins (Takada et al, 2007)] and sesquiterpene derivatives (Killday et al, 1993) have been isolated from sponges of the genus Poecillastra.…”