Cytotoxic Metabolites from an Indonesian Sponge Lendenfeldia sp.

Abstract

The lipid extract of an Indonesian Lendenfeldia sp. sponge inhibited hypoxia-induced hypoxiainducible factor-1 (HIF-1) activation in T47D breast tumor cells. Chromatographic separation yielded the new substituted naphthalene dimer 1, the new furanolipid 2, and three known Marine natural products continue to be an invaluable source of new molecular-targeted antitumor agents. 1 An ongoing research program was initiated to discover potent and selective small molecule inhibitors of hypoxia-mediated tumor cell adaptation, survival and metastatic spread. 2 The primary molecular target for this drug discovery effort is the transcription factor hypoxia-inducible factor-1 (HIF-1), a heterodimer composed of the oxygen-regulated HIF-1α and the constitutively expressed HIF-1β subunits. 3 Numerous studies strongly support HIF-1 as a valid molecular target for drug discovery that targets tumor hypoxia. 4 Terrestrial and marine organisms have been shown to produce natural products that inhibit HIF-1. 5 The NCI Open Repository of marine invertebrates and algae lipid extracts was examined for HIF-1 inhibitory activity using a T47D human breast carcinoma cell-based reporter assay. 2 The crude extract of the sponge Lendenfeldia sp. (Spongiidae) inhibited hypoxia-induced HIF-1 activation (99% inhibition at 5 μg mL -1 ).The extract (4 g) was purified by silica gel column chromatography and preparative TLC to yield two structurally unrelated new compounds (1 and 2) and three known homoscalarane sesterterpenes (3 -5). The 1 H-13 C HMBC spectrum of 1 exhibited long-range correlations from C-2 to H-3, H-4, C-2-OCH 3 ; from C-1 to H-3, H-8; from C-5 to H-4, H-7; from C-9 to H-4, H-7, H-8; and from C-10 to H-3, H-4, and H-8. Therefore, the substitution pattern for each of the symmetrically substituted naphthalene ring systems was readily established. Compound 1 was optically active ([α] 25 D +10.4). The CD spectrum displayed a positive split Cotton effect indicating that 1 exhibits a right-handed helicity, signifying "S"-configuration. Thus, the structure of 1 was determined to be (S)-2,2′-dimethoxy-1,1′-binaphthyl-5,5′,6,6′-tetraol.Compound 2 was isolated as colorless oil. The HRESIMS indicated that the molecular formula of 2 is C 21 H 34 O. The 1 H NMR spectrum (Table 2) exhibited resonances typical of a β-substituted furan [δ 7.33 (1H, brs), 7.20 (1H, brs), 6.27 (1H, brs)]. The 13 C NMR spectrum (Table 2) contained resonances for 21 carbons, and the 13 C DEPT spectrum indicated the presence of three methyl, ten methylene, five methane, and three quaternary carbon atoms. Analysis of the 1 H-1 H COSY and 1 H-13 C HMQC spectra suggested that the structure of 2 contained four spin systems: -CH(1)-CH(2)-, -CH 2 (5)-CH 2 (6)-CH (7) H spin systems were connected through the observation of longrange 1 H-13 C correlations in the HMBC spectrum from C-3 to H-1, H-2, H-4, H-5, H-6; from C-8 to H-6, H-7, H-9, H-10, H-20; and from C-12 to H-10, H-11, H-13, H-14, H-21. Therefore, the structure was deduced to be that of a new furanolipid.The ...

Latrunculin A and Its C-17-O-Carbamates Inhibit Prostate Tumor Cell Invasion and HIF-1 Activation in Breast Tumor Cells

“…The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates hypoxia-induced gene expression in tumor cells that are subjected to hypoxic conditions. 16b Disruption of HIF-1-mediated hypoxic adaptation/survival reduces tumor growth in animal models.16c-i HIF-1 inhibitors represent potential anticancer drug leads that may selectively target hypoxic tumor masses.16j-k The effects of 1-6 on hypoxia (1% O 2 )-induced HIF-1 activation were examined using a T47D human breast carcinoma cell-based luciferase reporter assay, 17 and compared to those observed on 1,10-phenanthroline-induced HIF-1 activation. Compound 1 inhibited hypoxia-induced activation (IC 50 6.7 µM, Figure 4) and 1,10-phenanthroline induced HIF-1 activation (IC 50 25 µM, data not shown).…”

Peroxy natural products

“…57 Bioassay-guided isolation of D. Levii collected from Papua New Guinea led to the isolation of four norsesterterpene peroxides, diacarnoxides A-D 108-111, with diacarnoxides A and B displaying cytotoxic properties and increased activity under hypoxic conditions. 58 Investigation of a southern Australian sponge of the genus Mycale resulted in the isolation of one norsesterterpene mycaperoxide G methyl ester 137, which was obtained after treatment of the crude extract with diazomethane. 69 The absolute stereochemistry previously assigned to mycaperoxide F methyl ester by application of the Horeau procedure has been revised by application of the Mosher procedure in the same paper.…”

Practical synthesis of polysubstituted naphthalene derivatives via HNTf2-catalyzed benzannulation reaction

“…The desired naphthalene 5v was obtained as a pale orange solid (118 mg, 34% yield 2-Bromo-1,4-diphenylnaphthalene (6). Starting from diphenylacetaldehyde 1i (196 mg, 1.0 mmol) and 2-bromoethynylbenzene 4u (272 mg, 1.5 mmol) and following the general procedure, the crude material was purified by flash column chromatography on silica gel using petroleum ether as eluent.…”

“…[1][2][3][4][5][6][7][8][9] Additionally, this particular aromatic structure can be found in numerous optical and electronic materials [10][11][12] and constitutes the backbone of many chiral ligands. 13 Nafacillin, 14 suramin, 15,16 which play a vital role in the control of microbial infection, are typical examples of drugs that present a naphthalene moiety ( Figure 1).…”