Isolation and Cytotoxic Evaluation of Marine Sponge-Derived Norterpene Peroxides

Abstract

The marine sponge Diacarnus cf. spinopoculum has provided a series of norterpenes, including five new compounds (7-11), two new ent-compounds [(-)-1a and (+)-1b], and three known compounds (2a, 2b, and 12). Eight of these compounds represent additional examples of the muqubilin/sigmosceptrellin classes (norsesterterpene peroxides) or the nuapapuin class (norditerpene peroxides). Also isolated were dinorditerpenones 11 and 12, which are biosynthetically related to the muqubilin/sigmosceptrellin structure classes. In all, 11 compounds were evaluated for their cytotoxic properties using a soft agar assay system and the NCI's 60 cell-line screen. Compounds without peroxide functionality were inactive. Overall, the norsesterterpene peroxides were less selective as cytotoxins than norditerpene peroxide analogues. Two compounds, nuapapuin A methyl ester (3) and nuapapuin B (7), which were somewhat selective in their cytotoxic behavior, were selected for further in vivo evaluation.

Hypoxia-Selective Antitumor Agents: Norsesterterpene Peroxides from the Marine Sponge Diacarnus levii Preferentially Suppress the Growth of Tumor Cells under Hypoxic Conditions

“…Comparison of the NMR spectra of 2 (Tables 1 and 2) with those of 1 revealed that 2 possesses a similar structure, except for the absence of the resonances for the C-1 methyl ester observed in 1. The downfield shift in the 13 C resonance observed for C-1 in 2 (δ = 180.1 ppm), relative to the δ = 174.2 ppm observed for C-1 in 1, was consistent with a proposed structure that contains a C-1 carboxylic acid. The HRESIMS mass spectrum of 2 displayed a molecular ion that was 14 mass units less than that observed for 1.…”

“…The 1 H, 13 C and 13 C DEPT NMR spectra of 3 (Tables 1, 2) were closely related to those of 1. The 13 C NMR spectrum of 3 (Table 2) exhibited seven methyl, ten methylene, three methine, and five quaternary carbon resonances.…”

“…Compound (1) These proton-proton spin systems were readily assembled by analysis of long-range 1 H- 13 C couplings that were observed in the 1 H-13 C HMBC spectrum between C-1 and H-2, H-19, C-1-OCH 3 ; between C-6 and H-4, H-5, H-7, H-20; between C-14 and H-13, H-15, H-16, H-22; and between C-18 and H-13, H-16, H-17, H-23, H-24 (Fig. 1).…”

New Metabolites from the South China Sea Sponge <i>Diacarnus megaspinorhabdosa</i>

“…1) Sponges of genus Diacarnus are recognized as being prolific sources to produce terpene peroxides and related derivatives, which include norterpene ketones, dienes, diols and other types of compounds. [2][3][4][5][6][7][8] From a biosynthetic perspective, the biosynthetic origin of some or all marine norterpene cyclic peroxides involved a common intermediate C6 hydroperoxide, undergoing a "Michael addition" to an adjacent α,β-unsaturated carboxylic acid or ester moiety. 6) As an offshoot of the biosynthetic pathway, the norterpene ketones can be derived from the hydroperoxide carboxylic aid precursor by oxidative degradation.…”

“…6) Such ketones are increasingly being identified as minor co-metabolites with norterpene cyclic peroxides. 3,[9][10][11] Recently, attention has been drawn on these metabolites because of their pharmaceutical properties, including antimalarial, 8,12) antimicrobial, 12) Trypanosoma brucei inhibitory, 13) sea urchin egg cell-division inhibitory, 14) cytotoxic, 4,7,15) antiulcer and antihypotensive activities. 16) As our previous chemical research on the sponge D. megaspinorhabdosa, five norterpene cyclic peroxides diacarperoxides H-L have been isolated.…”