Heegyu Kim

Ohmyungsamycins A and B: cytotoxic and antimicrobial cyclic peptides produced by Streptomyces sp. from a volcanic island.

Ohmyungsamycins A and B (1 and 2), which are new cyclic peptides, were isolated from a marine bacterial strain belonging to the Streptomyces genus collected from a sand beach on Jeju, a volcanic island in the Republic of Korea. Based on the interpretation of the NMR, UV, and IR spectroscopic and MS data, the planar structures of 1 and 2 were elucidated as cyclic depsipeptides bearing unusual amino acid units, including N-methyl-4-methoxytrytophan, β-hydroxyphenylalanine, and N,N-dimethylvaline. The absolute configurations of the α-carbons of the amino acid residues were determined using the advanced Marfeys method. The configurations of the additional stereogenic centers at the β-carbons of the threonine, N-methylthreonine, and β-hydroxyphenylalanine units were assigned by GITC (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate) derivatization and the modified Moshers method. We have developed a new method utilizing PGME (phenylglycine methyl ester) derivatization coupled with chromatographic analysis to determine the absolute configuration of N,N-dimethylvaline. Our first successful establishment of the absolute configuration of N,N-dimethylvaline using PGME will provide a general and convenient analytical method for determining the absolute configurations of amino acids with fully substituted amine groups. Ohmyungsamycins A and B showed significant inhibitory activities against diverse cancer cells as well as antibacterial effects.

Mohangamides A and B, new dilactone-tethered pseudo-dimeric peptides inhibiting Candida albicans isocitrate lyase.

Mohangamides A and B (1-2) were discovered from a marine Streptomyces sp. collected in an intertidal mud flat. The structures of the compounds were elucidated as novel dilactone-tethered pseudodimeric peptides bearing two unusual acyl chains and 14 amino acid residues based on comprehensive spectroscopic analysis. The absolute configurations of the mohangamides were determined by chemical derivatizations, followed by chromatographic and spectroscopic analyses. Mohangamide A displayed strong inhibitory activity against Candida albicans isocitrate lyase.

Gombaspiroketals A–C, Sesterterpenes from the Sponge Clathria gombawuiensis

Gombaspiroketals A-C (1-3), tetracyclic sesterterpenes of a novel skeletal class, were isolated from the Korean marine sponge Clathria gombawuiensis. On the basis of the combined spectroscopic analyses, the structures of these compounds were determined to be highly rearranged sesterterpene spiroketal methoxyacetals (1 and 2) and a corresponding hemiacetal (3). The relative and absolute configurations were assigned by NOESY analysis and ECD calculations, respectively. These compounds exhibited moderate cytotoxicities and antibacterial activities.

Separacenes A-D, Novel Polyene Polyols from the Marine Actinomycete, Streptomyces sp.

Separacenes A–D (1–4), novel polyene polyols, were isolated from Streptomyces sp. collected from the southern area of Jeju Island, Korea. The chemical structures of 1–4 were established by NMR, mass, UV, and IR spectroscopy as well as the modified Mosher’s method. Separacenes A–B (1–2), which share an identical planar structure but possess different relative configurations, bear tetraene units flanked by two diol moieties, whereas the stereoisomeric separacenes C–D (3–4) possess a triene moiety between two diol substructures. Separacenes A–D each contain a terminal olefinic methylene. Separacene A displayed inhibitory activity against Candida albicans isocitrate lyase and weak cytotoxicity against both the colon carcinoma cell line HCT-116 and the lung cancer cell line A549.

Inhibition of Candida albicans isocitrate lyase activity by cadiolides and synoilides from the ascidian Synoicum sp.

Tris-aromatic furanones (1-4) and related bis-aromatic diesters (5 and 6) isolated from the dark red ascidian Synoicum sp., were evaluated for their inhibitory activities toward Candida albicans isocitrate lyase (ICL). These studies led to the identification of compounds 1, 3, and 4 as potent ICL inhibitors, with IC50 values of 7.62, 17.16, and 10.36 μM, respectively. Growth phenotype of ICL deletion mutants and Northern blot analysis data indicated that compound 1 inhibits the ICL expression in C. albicans under C2 carbon utilizing condition.

Cytotoxic Diterpenoid Pseudodimers from the Korean Sponge Phorbas gukhulensis

Four new cytotoxic diterpenoid pseudodimers (2-5), along with a previously reported one, gukulenin A (1), were isolated from the marine sponge Phorbas gukhulensis collected off the coast of Gagu-do, Korea. These novel compounds, designated gukulenins C-F (2-5), were determined by extensive spectroscopic analyses to be pseudodimers of the gagunins, like gukulenin A. The termini of the tropolone-containing side chains in gukulenins C-E (2-4) were found to have diverse modifications involving acetamides or taurine, whereas gukulenin F (5) was formed from 1 by the ring-opening of a cyclic hemiketal. The relative and absolute configurations were assigned by Muratas and modified Snatzkes methods using a HETLOC experiment and a CD measurement of a dimolybdenum complex, respectively. All of these compounds exhibited significant cytotoxicity against the K562 and A549 cell lines.

Manzamine Alkaloids from an Acanthostrongylophora sp. Sponge

Five new manzamine alkaloids (1-5) and new salt forms of two known manzamines (6 and 7), along with seven known compounds (8-14) of the same structural class, were isolated from an Indonesian Acanthostrongylophora sp. sponge. On the basis of the results of combined spectroscopic analyses, the structure of kepulauamine A (1) was determined to possess an unprecedented pyrrolizine moiety, while others were functional group variants of known manzamines. These compounds exhibited weak cytotoxicity, moderate antibacterial activity, and mild inhibition against the enzyme isocitrate lyase.

Bahamaolide A from the marine-derived Streptomyces sp. CNQ343 inhibits isocitrate lyase in Candida albicans.

Bahamaolide A, a new macrocyclic lactone isolated from the culture of marine actinomycete Streptomyces sp. CNQ343, was evaluated for its inhibitory activity toward isocitrate lyase (ICL) from Candida albicans. These studies led to the identification of bahamaolide A as a potent ICL inhibitor with IC50 value of 11.82 μM. The growth phenotype of ICL deletion mutants and quantitative RT-PCR analyses indicated that this compound inhibits the ICL mRNA expression in C. albicans under C2-carbon-utilizing conditions. The present data highlight the potential for bahamaolide A treatment of C. albicans infections via inhibition of ICL activity.

A farnesoic acid‐responsive transcription factor, Hot1, regulates yeast‐hypha morphogenesis in Candida albicans

Candida albicans hyphal formation is inhibited by a quorum‐sensing molecule, farnesoic acid, which accumulates in the medium as the cells proliferate. We recently showed that Pho81 is essential for the inhibition of hyphal growth by farnesoic acid. Here, we describe a newly identified regulator, Hot1, which increases the expression of PHO81. The binding site of Hot1 in the PHO81 promoter region was identified by DNase I protection assay. The hot1Δ mutant grows extensively as filaments. Furthermore, the inhibition of hyphal formation and the repression of major signaling pathway components in response to farnesoic acid are defective in hot1Δ mutant cells. These data suggest an important role for HOT1 in the inhibition of hyphal development by farnesoic acid in this fungus.