Petrosaspongiolides M−R:  New Potent and Selective Phospholipase A₂ Inhibitors from the New Caledonian Marine Sponge Petrosaspongia nigra

Abstract

Five new bioactive sesterterpenes (1-5) have been isolated from the New Caledonian marine sponge Petrosaspongia nigra Bergquist and named petrosaspongiolides M-R. Their chemical structures were determined from 1D and 2D NMR studies and MS data. All compounds inhibited different preparations of phospholipase A2 (PLA2) by irreversibly blocking these enzymes (particularly human synovial and bee venom, see Table 3), with IC50 values in the micromolar range. Interestingly, these compounds displayed a much lower activity (or no activity at all) toward porcine pancreas and Naja naja venom PLA2 enzymes. The most potent compound, 1 (IC50 1.6 and 0.6 microM for human synovial and bee venom PLA2 enzymes, respectively), was slightly more active than manoalide (6) (IC50 3.9 and 7.5 microM) under our experimental conditions. Compound 3 is more selective, inhibiting human synovial PLA2 to a greater extent than bee venom PLA2.

Stereochemistry of Antiinflammatory Marine Sesterterpenes

“…Petrosaspongiolide M (25) [25] and cavernosolide (26) [26] are tetracyclic sesterterpenes related to manoalide for which only the relative stereochemistry on the tetracyclic nucleus has been established by NMR data.…”

“…The mixture was poured into H 2 O, extracted with AcOEt, and the crude product was purified by SiO 2 column chromatography (Et 2 O/petroleum ether, 7:3) to give 23 (9 mg) and 24 (2.7 mg). Diacetates 9, 10, 12, 13, 27, 28, 29, 30: The diacetates of cacospongionolide (9, 10), [9] cacospongionolide B (12, 13), [3] petrosaspongiolide M (27, 28), [25] and cavernosolide (29, 30), [26] were prepared as previously described.…”

PLA2‐mediated catalytic activation of its inhibitor 25‐acetyl‐petrosaspongiolide M: serendipitous identification of a new PLA2suicide inhibitor

“…In fact, armed with such knowledge, we aim at a rational design of simplified inhibitors of PLA 2 as potential new leads for the treatment of inflammation-related diseases [11][12][13][14][15][16][17][18][19]. In this context, bvPLA 2 represents a very useful model for such studies, as the pharmacological characterization of PM and its derivatives has shown an excellent correlation between inhibitory profiles obtained on this model (group III) enzyme with respect to (group IIa) human secretory counterpart (hsPLA 2 ) [8,20].…”

Synthetic approaches toward sesterterpenoids

“…Since then, Fekih et al 118 reported the semisynthesis of the cheilanthane sesterterpenoid ( ) petro saspongianolide R (199). 119 The synthesis of another tricarbocyclic sesterterpenoid, ( ) nitiol (200) (Fig. 11), 120 a potent enhancer of IL 2 gene expression in human T cell lines, was attempted, and almost achieved, by Dake and co workers.…”