Eric H. Andrianasolo

Structural and Synthetic Investigations of Tanikolide Dimer, a SIRT2 Selective Inhibitor, and Tanikolide Seco Acid from the Madagascar Marine Cyanobacterium Lyngbya majuscula

Tanikolide seco-acid 2 and tanikolide dimer 3, the latter a novel and selective SIRT2 inhibitor, were isolated from the Madagascar marine cyanobacterium Lyngbya majuscula. The structure of 2, isolated as the pure R enantiomer, was elucidated by X-ray experiment in conjunction with NMR and optical rotation data, whereas the depside molecular structure of 3 was initially thought to be a meso compound as established by NMR, MS, and chiral HPLC analyses. Subsequent total synthesis of the three tanikolide dimer stereoisomers 4, 5, and ent-5, followed by chiral GC-MS comparisons with the natural product, showed it to be exclusively the R,R-isomer 5. Tanikolide dimer 3 (= 5) inhibited SIRT2 with an IC(50) = 176 nM in one assay format and 2.4 microM in another. Stereochemical determination of symmetrical dimers such as compound 3 pose intriguing and subtle questions in structure elucidation and, as shown in the current work, are perhaps best answered in conjunction with total synthesis.

Apoptosis-inducing galactolipids from a cultured marine diatom, Phaeodactylum tricornutum.

Two monogalactosyl diacylglycerols, 1 and 2, were isolated from the marine diatom Phaeodactylum tricornutum, using the patented ApopScreen cell-based screen for apoptosis-inducing, potential anticancer compounds. The molecular structures of the galactolipids were determined using a combination of NMR, mass spectrometry, and chemical degradation. The bioactivities were confirmed using a specific apoptosis induction assay based on genetically engineered mammalian cell lines with differential, defined capacities for apoptosis. The galactolipids induce apoptosis in micromolar concentrations. This is the first report of apoptosis induction by galactolipids.

Ammonificins A and B, Hydroxyethylamine Chroman Derivatives from a Cultured Marine Hydrothermal Vent Bacterium, Thermovibrio ammonificans

Two hydroxyethylamine chroman derivatives, ammonificins A (1) and B (2), were isolated from the marine hydrothermal vent bacterium Thermovibrio ammonificans. The molecular structures of these compounds were determined using a combination of NMR, mass spectrometry, and CD analyses. Biological activities were determined using an antimicrobial assay and the patented ApopScreen cell-based screen for apoptosis induction and potential anticancer activity. To our knowledge, this is the first report of secondary metabolites from the marine hydrothermal vent bacterium T. ammonificans.

Mitsoamide: A cytotoxic linear lipopeptide from the Madagascar marine cyanobacterium Geitlerinema sp.*

A new cytotoxic and linear peptide (IC50 460 nM to NCI-H460 human lung tumor cells) was isolated from the marine cyanobacterium Geitlerinema sp. The planar structure of mitsoamide was deduced by 1D and 2D NMR experiments in combination with MS analyses. The structure of mitsoamide contains an unusual polyketide unit (3,7-dimethoxy-5-methyl-nonanedioic acid, DMNA), incorporates a homolysine (HomoLys) residue and possesses a highly unusual piperidine aminal moiety. The configurations of the relatively common amino acids present in mitsoamide (Ala, Ile, N-Me-Ile, Phe, Val) were determined by chiral HPLC analysis of the acid hydrolysate.

Ammonificins C and D, Hydroxyethylamine Chromene Derivatives from a Cultured Marine Hydrothermal Vent Bacterium, Thermovibrio ammonificans

Chemical and biological investigation of the cultured marine hydrothermal vent bacterium, Thermovibrio ammonifican led to the isolation of two hydroxyethylamine chromene derivatives, ammonificins C and D. Their structures were elucidated using combination of NMR and mass spectrometry. Absolute stereochemistry was ascertained by comparison of experimental and calculated CD spectra. Biological evaluation and assessment were determined using the patented ApopScreen cell-based screen for apoptosis-induction. Ammonificins C and D induce apoptosis in micromolar concentrations. To our knowledge, this finding is the first report of chemical compounds that induce apoptosis from the cultured deep-sea marine organism, hydrothermal vent bacterium, Thermovibrio ammonificans.

Bathymodiolamides A and B, Ceramide Derivatives from a Deep-Sea Hydrothermal Vent Invertebrate Mussel, Bathymodiolus thermophilus

Two ceramide derivatives, bathymodiolamides A (1) and B (2), were isolated from the deep-sea hydrothermal vent invertebrate mussel Bathymodiolus thermophilus. The molecular structures of these compounds were determined using a combination of NMR spectroscopy, mass spectrometry, and chemical degradation. Biological activities were assessed in a ApopScreen cell-based screen for apoptosis induction and potential anticancer activity. To our knowledge, this is the first report of secondary metabolites from the marine hydrothermal vent mussel B. thermophilus.

Mode of action of diterpene and characterization of related metabolites from the soft coral, Xenia elongata.

Chemical and biological investigation of the cultured marine soft coral Xenia elongata led to the isolation of two new diterpenes (2, 3). Their structures were elucidated using a combination of NMR and mass spectrometry. Biological evaluations and assessments were determined using the specific apoptosis induction assay based on genetically engineered mammalian cell line D3 deficient in Bak and Bax and derived from a mouse epithelial cell. The diterpenes induce apoptosis in low micromolar concentrations. The results indicate that the previously isolated compound (1) affects cell in a manner similar to that of HSP90 and HDAC inhibitors and in a manner opposite of PI3 kinase/mTOR inhibitors. Compound (3) inhibits selectively HDAC6 in high micromolar concentrations.

Chapter 3 – Deep-Sea Hydrothermal Vents as a New Source of Drug Discovery

There are potentially thousands of natural compounds that can induce a cell death cascade or arrest cell division, and strategic searches for such molecules have led to drugs discoveries with major clinical applications. Far less than 1% of the extracts of marine organisms have been screened for anticancer activity. Because of the dependence of stationary marine organisms on biochemical defense mechanisms, bioactive marine natural products are plentiful, often structurally unique, with no counterparts in terrestrial organisms. Thus, the oceans represent a rich, but largely untapped, resource for biologically active, anticancer compounds. In this review, we discuss the potential of deep-sea hydrothermal vents as a hot spot for bioactive marine natural products discovery. We then display the main mechanism of apoptosis induction and develop a new strategy for anticancer and drug discovery approach. We develop in detail the first isolation and structural elucidation of metabolites from marine organisms associated with deep-sea hydrothermal vents (the marine hydrothermal vent bacterium, Thermovibrio ammonificans and the deep-sea hydrothermal vent invertebrate mussel, Bathymodiolus thermophilus). We conclude with the uniqueness of metabolites that induce apoptosis such as the Xenia elongata compounds series.