Masayoshi Arai

Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria

Three new aminolipopeptides, designated trichoderins A (1), A1 (2), and B (3), were isolated from a culture of marine sponge-derived fungus of Trichoderma sp. as anti-mycobacterial substances with activity against active and dormant bacilli. The chemical structures of trichoderins were determined on the basis of spectroscopic study. Trichoderins showed potent anti-mycobacterial activity against Mycobacterium smegmatis, Mycobacterium bovis BCG, and Mycobacterium tuberculosis H37Rv under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions, with MIC values in the range of 0.02-2.0 microg/mL.

Pyrazinoic Acid and Its n-Propyl Ester Inhibit Fatty Acid Synthase Type I in Replicating Tubercle Bacilli

ABSTRACT The activity of different analogs of pyrazinamide on Mycobacterium tuberculosis fatty acid synthase type I (FASI) in replicating bacilli was studied. Palmitic acid biosynthesis was diminished by 96% in bacilli treated with n-propyl pyrazinoate, 94% in bacilli treated with 5-chloro-pyrazinamide, and 97% in bacilli treated with pyrazinoic acid, the pharmacologically active agent of pyrazinamide. We conclude that the minimal structure of pyrazine ring with an acyl group is sufficient for FASI inhibition and antimycobacterial activity.

Lariatins, Novel Anti-mycobacterial Peptides with a Lasso Structure, Produced by Rhodococcus jostii K01-B0171

Two anti-mycobacterial peptides with a lasso structure, named lariatins A and B, were separated by HP-20 and ODS column chromatographies and purified by HPLC from the culture broth of Rhodococcus jostii K01-B0171, which was isolated from soil aggregates collected in Yunnan, China. Lariains A and B showed growth inhibition against Mycobacterium smegmatis with MIC values of 3.13 and 6.25 μg/ml in agar dilution method, respectively. Furthermore, lariatin A inhibited the growth of Mycobacterium tuberculosis with an MIC of 0.39 μg/ml in liquid microdilution method.

Hypoxia‐Selective Growth Inhibition of Cancer Cells by Furospinosulin‐1, a Furanosesterterpene Isolated from an Indonesian Marine Sponge

It is generally accepted that cancer cells, which have adapted to the hypoxic environments in tumor tissues, aggravate cancer pathology by promoting tumor growth, angiogenesis, metastasis, and drug resistance. Therefore, compounds that selectively inhibit the growth of tumor cells in hypoxic environments are expected to provide new leads for promising anticancer drugs. Furospinosulin‐1, a marine‐sponge‐derived furanosesterterpene, exhibited selective antiproliferative activity against DU145 human prostate cancer cells under hypoxic conditions in concentrations ranging from 1 to 100 μM. Furospinosulin‐1 also demonstrated antitumor activity at 10–50 mg kg−1 oral administration in a mouse model inoculated with sarcoma S180 cells. Mechanistic analysis revealed that furospinosulin‐1 suppresses transcription of the insulin‐like growth factor‐2 gene (IGF‐2), which is selectively induced under hypoxic conditions through prevention of the binding of nuclear proteins to the Sp1 consensus sequence in the IGF‐2 promoter region.

Stylissamide X, a new proline-rich cyclic octapeptide as an inhibitor of cell migration, from an Indonesian marine sponge of Stylissa sp.

A new proline-rich cyclic octapeptide named stylissamide X (1) was isolated from an Indonesian marine sponge of Stylissa sp. as an inhibitor of cell migration from the guidance of wound-healing assay. The chemical structure of stylissamide X (1) was determined on the basis of spectroscopic analysis, and stereostructure of the amino acids were deduced by Marfeys method. Compound 1 showed inhibitory activity against migration of HeLa cells in the ranges of 0.1-10 μM concentration through both wound-healing assay and chemotaxicell chamber assay, while the cell viability was maintained more than 75% up to 10 μM concentration of 1.

Neamphamide B, new cyclic depsipeptide, as an anti-dormant mycobacterial substance from a Japanese marine sponge of Neamphius sp.

A new cyclic depsipeptide, designated neamphamide B (1), was isolated from a marine sponge of Neamphius sp. collected at Okinawa, Japan in 1993 as an anti-mycobacterial substance against active and dormant bacilli. The planar structure of neamphamide B (1) was determined on the basis of spectroscopic analysis, and stereostructure of amino acid was deduced by chromatographic comparison of the acid hydrolysate of 1 with appropriate amino acid standards after derivatizing with FDAA or GITC. Neamphamide B (1) showed potent anti-mycobacterial activity against Mycobacterium smegmatis under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions with MIC of 1.56 μg/mL. Neamphamide B (1) was also effective to Mycobacterium bovis BCG with MIC in the ranging of 6.25-12.5 μg/mL.

DedA Protein Relates to Action-Mechanism of Halicyclamine A, a Marine Spongean Macrocyclic Alkaloid, as an Anti-dormant Mycobacterial Substance

A macrocyclic alkaloid, halicyclamine A, was re-discovered from an Indonesian marine sponge of Haliclona sp. 05A08 as an anti-dormant mycobacterial substance. To clarify action-mechanism of halicyclamine A, halicyclamine A-resistant strains were screened from the transformants of Mycobacterium smegmatis with the genomic DNA library of M. bovis BCG, which were constructed in the multi-copy shuttle cosmid pYUB145. Sequencing analysis of the cosmids isolated from the halicyclamine A-resistant transformants revealed that the responsible gene was involved in the genome region between 2920.549 kb and 2933.210 kb. Further experiments using the transformants over-expressing individual gene contained in the responsible region were executed, and the transformant, which over-expressed BCG2664 gene assigned as dedA gene, was found to become halicyclamine A-resistant. This evidence strongly suggested that DedA protein correlates with the action-mechanism of halicyclamine A as an anti-dormant mycobacterial substance.

Dysideamine, a new sesquiterpene aminoquinone, protects hippocampal neuronal cells against iodoacetic acid-induced cell death

In the course of our search for neuroprotective agents, dysideamine (1), a new sesquiterpene aminoquinone, was isolated along with bolinaquinone (2) from Indonesian marine sponge of Dysidea sp. Compounds 1 and 2 showed neuroprotective effect against iodoacetic acid (IAA)-induced cell death at 10 microM concentration in mouse HT22 hippocampal neuronal cells. Dysideamine (1) inhibited production of reactive oxygen species (ROS) by IAA treatment, whereas it exhibited no effect on depletion of intracellular ATP of the IAA-treated HT22 cells. Moreover, 1 induced neurite outgrowth against mouse neuroblastoma Neuro 2A cells with increase of acetylcholinesterase (AChE) activity, which is a marker of neuronal differentiation.

Prenylterphenyllin and Its Dehydroxyl Analogs, New Cytotoxic Substances from a Marine-derived Fungus Aspergillus candidus IF10

Three novel cytotoxic substances named prenylterphenyllin (1), 4″-deoxyprenylterphenyllin (2), and 4″-deoxyisoterprenin (3) were isolated from a cultured marine-derived fungus of Aspergillus candidus IF10 together with 4″-deoxyterprenin (4). Their chemical structures were elucidated on the basis of 2D NMR analysis. These compounds 1~4 showed cytotoxic activity against human epidermoid carcinoma KB cells (KB3-1) with IC50 of 8.5, 3.0, 2.5, and 4.5 μg/ml, respectively.

Marine spongian sesquiterpene phenols, dictyoceratin-C and smenospondiol, display hypoxia-selective growth inhibition against cancer cells.

In the course of our search for hypoxia-selective growth inhibitors against cancer cells, a sesquiterpene phenol, dictyoceratin-C (1), was isolated from the Indonesian marine sponge of Dactylospongia elegans under the guidance of the constructed bioassay. Dictyoceratin-C (1) inhibited proliferation of human prostate cancer DU145 cells selectively under hypoxic condition in a dose-dependent manner at the concentrations ranging from 1.0 to 10 μM. The subsequent structure-activity relationship study using nine sesquiterpene phenol/quinones (2-10), which were isolated from marine sponge, was executed. We found that smenospondiol (2) also exhibited the similar hypoxia-selective growth inhibitory activity against DU145 cells, and the para-hydroxybenzoyl ester moiety would be important for hypoxia-selective growth inhibitory activity of 1. In addition, the mechanistic analysis of dictyoceratin-C (1) revealed that the 10 μM of 1 inhibited accumulation of Hypoxia-Inducible Factor-1α under hypoxic condition.