Campechic acids A and B: anti-invasive polyether polyketides from a soil-derived Streptomyces.

Campechic acids A (1) and B (2), two new polyketides, were isolated from the culture extract of Streptomyces sp., and their structures were determined by NMR and MS spectroscopic analysis. Campechic acids are polyether-polyketides functionalized by two tetrahydrofuran rings, an enolized 1,3-diketone, and multiple methyl substitutions. Absolute configuration of nine stereogenic centers in 1, except for four chiral centers in the cyclic ether moieties, was determined by the 1H NMR anisotropy method in combination with chemical degradation. Campechic acids exhibited potent inhibitory effects on tumor cell invasion with IC50 values in the nanomolar to submicromolar range.

Complete stereochemistry and preliminary structure-activity relationship of rakicidin A, a hypoxia-selective cytotoxin from Micromonospora sp.

The complete stereochemistry of rakicidin A, a hypoxia-selective cytotoxin produced by Micromonospora sp., was unambiguously established by extensive chemical degradation and derivatization studies. During the PGME derivatization-based configurational analysis of 3-hydroxy-2,4,16-trimethylheptadecanoic acid, an irregular Δδ distribution was observed, which necessitated further acylation of the 3-hydroxy group to resolve the inconsistency. A hydrogenated derivative of rakicidin A, its ring-opened product, and two congeners with different alkyl chain lengths were tested for hypoxia-selective cytotoxicity. The results indicated that both the conjugated diene unit and appropriate chain length are essential for the unique activity of rakicidin A.

Synthesis and evaluation of trehalose-based compounds as anti-invasive agents.

Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to explore the preliminary structure-activity relationship and obtain more potent inhibitors, a series of brartemicin analogs were synthesized through the Mitsunobu coupling of the secondary hydroxyls benzyl protected α,α-D-trehalose with benzoic acid derivatives, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells in vitro. Among the synthetic analogs tested, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose (5e) was found to be the most potent anti-invasive agent, exhibited a 2.6-fold improvement with regard to the parent natural product brartemicin, and it is considered to be a promising lead molecule for the anti-metastasis.

Lupinacidin C, an inhibitor of tumor cell invasion from Micromonospora lupini.

A new anthraquinone derivative, lupinacidin C (1), was isolated from the endophytic actinomycete Micromonospora lupini. The structure was elucidated on the basis of spectroscopic analyses, and the absolute configuration was determined by total synthesis. Lupinacidin C (1) exhibited the most potent inhibitory effects among the congeners on the invasion of murine colon carcinoma cells into the reconstituted basement membrane.

Anti-invasive and anti-angiogenic activities of naturally occurring dibenzodiazepine BU-4664L and its derivatives.

In the screening for antitumor leads from microbial secondary metabolites, BU-4664L (1), a naturally occurring dibenzodiazepine, was found to inhibit tumor invasion and angiogenesis in vitro. Compound 1 inhibited the gelatinase activities of MMP-2 and MMP-9 and the cellular motility. Four derivatives (2-5) were synthesized from 1 and their antitumor activities were evaluated. Compounds 3 and 4 exhibited potent anti-angiogenic effects on HUVEC, together with remarkable inhibition of cell migration at nanomolar concentrations, and showed much lower cytotoxicity.

Abyssomicin I, a modified polycyclic polyketide from Streptomyces sp. CHI39.

Abyssomicin I (1), a new modified polycyclic polyketide, was isolated from the culture extract of a soil-derived Streptomyces sp. The structure of 1 was elucidated by interpretation of NMR and other spectroscopic data. The stereochemistry of the new compound was assigned by NOE analysis, chemical derivatization, and application of the modified Mosher method. While 1 was inactive against bacteria and yeasts, the oxidized derivative 7 showed weak activities against gram-positive bacteria. Compounds 1 and 7 exhibited inhibitory effects on tumor cell invasion with IC(50) values of 11 and 0.21 µM, respectively.

Synthesis and evaluation of myxochelin analogues as antimetastatic agents.

Myxochelin A (1) is an inhibitor of tumor cell invasion produced by the bacterium belonging to the genus Nonomuraea. In order to obtain more potent inhibitors, a series of myxochelin analogues [2 and (S)-3-17] were synthesized through the coupling of lysine or diaminoalkane derivatives and appropriately protected hydroxybenzoate, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells. Among the synthetic analogues tested, compound (S)-6 which possesses carbamoyl group at C-1 was found to be the most potent antiinvasive agent and is considered to be a promising lead molecule for the antimetastasis. Compound (S)-6 was also shown to inhibit gelatinase activities of MMP-2 and MMP-9 and in vivo lung metastasis in mice.

Brartemicin, an inhibitor of tumor cell invasion from the actinomycete Nonomuraea sp.

Brartemicin (1), a new trehalose-derived metabolite, was isolated from the culture broth of the actinomycete of the genus Nonomuraea. Its structure and absolute configuration were determined by spectroscopic analyses. The new compound inhibited the invasion of murine colon carcinoma 26-L5 cells with an IC(50) value of 0.39 microM in a concentration-dependent manner without showing cytotoxic effects.

Flazin as a Promising Nrf2 Pathway Activator.

Flazin is a ß-carboline-derived alkaloid found in Japanese fermented foods. Here, the potential of flazin as an antioxidant food was studied with particular reference to its effect on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system in human hepatocytes (C3A). Flazin and flazin analogues including the decarboxylated derivative perlolyrine were chemically synthesized and compared with each other and with chlorogenic acid and curcumin. Among these compounds, flazin showed the lowest cytotoxicity (IC50 < 500 µM) and the highest capacity to activate the Keap1-Nrf2 system. It provided the largest (>3-fold of the control) cytoprotection ability against a pro-oxidant, although its radical absorbance capacity was relatively low. Flazin increased the expressions of Nrf2-dependent phase II enzyme genes and their products (NQO1, GSTP, and GSH proteins). The strong cytoprotection ability of flazin associated with low log P (0-3) is shared by sulforaphane and 3,5-dihydroxy-4-methoxybenzyl alcohol, suggesting the potential value of flazin and flazin-rich foods for the prevention of oxidation-related health disorders.

Absolute configuration and antitumor activity of myxochelin A produced by Nonomuraea pusilla TP-A0861.

In the screening of antitumor compounds from microbial secondary metabolites, myxochelin A was isolated from a culture broth of Nonomuraea pusilla TP-A0861. The absolute configuration was determined to be S by synthesizing both enantiomers from an L- or D-lysine derivative and comparing their specific rotations. Both enantiomers of myxochelin A showed remarkable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells at non-cytotoxic concentrations.

A fatty acid profiling method using liquid chromatography-high resolution mass spectrometry for improvement of assisted reproductive technology.

BACKGROUND: Liquid chromatography-high resolution mass spectrometry (LC-HRMS) can be useful to improve in vitro fertilization (IVF). This study aims to find out an association between embryonic growth and embryonic uptake of free fatty acid (FFA) from culture media by using LC-HRMS. METHODS: Embryos (n=55) from 15 couples undergoing IVF were studied. An embryo was cultivated for up to 6 days in a 20 µl-medium drop under mineral oil, and classified by a morphological grading system into the good-growth group (n=32; good quality blastocysts) and the poor-growth group (n=23; non-blastocysts). The control study was set up without embryo. Extracted ion chromatogram of FFAs was collected in negative-ion mode for each medium sample obtained after use. RESULTS: The percent change from control to sample in mass area for docosahexaenoic acid showed a decrease in the good-growth group than that in the poor-growth group (p<0.05). Decrease in %change of docosahexaenoic acid might indicate proper embryonic growth. Similar but insignificant change was observed for other essential FFAs, but not for non-essential FFAs. CONCLUSION: The proposed metabolomic approach using LC-HRMS might be a powerful tool for non-invasive evaluation of embryonic growth.

Rapid tin-mediated access to a lysophosphatidylethanolamine (LPE) library: Application to positional LC/MS analysis for hepatic LPEs in non-alcoholic steatohepatitis model mice.

Even though lysophospholipids have attracted much interest in recent years on account of their unique bioactivity, research related to lysophospholipids is usually hampered by problems associated with standard sample preparation and discrimination of regioisomers. Herein, we demonstrate a quick tin-chemistry-based synthetic route to lysophosphatidylethanolamines (LPEs) and its application in the positional analysis of hepatic LPEs in non-alcoholic steatohepatitis (NASH) model mice. We found that the preference of hepatic LPE regioisomer largely depends on the unsaturation of acyl chain in both control and NASH model mice. In addition, hepatic C18:2-LPE and C20:5-LPE levels were significantly lower in the NASH model mice than those in the control. The LC/MS technique based on the library of LPE regioisomers allows an accurate observation of hepatic LPE metabolism and might provide useful information to elucidate yet ambiguous pathogenesis of NASH.

Revision of the structure assigned to the antibiotic BU-4664L from Micromonopora.

The structure assigned to the antitumor antibiotic BU-4664L from Micromonospora sp. was revised to 5,10-dihydro-4,6,8-trihydroxy-10-(3,7,11-trimethyl-trans-2,trans-6,10-dodecatrienyl)-11H-dibenzo[b,e] [1,4]-diazepin-11-one based on the NMR analysis.

Synthesis and structure-activity relationships studies of brartemicin analogs as anti-invasive agents.

Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to find more potent anti-invasive agents and study the structure-activity relationships, a series of 19 brartemicin analogs were prepared via two synthetic routes from α,α-D-trehalose and evaluated for their anti-invasive activities. Compound 4f, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, was more potent than the natural brartemicin. It inhibited the invasion of murine colon 26-L5, colon carcinoma SW620, melanoma B16-BL6 and breast MDA-MB-231 cells with IC50 values of 0.15, 2.35, 4.12 and 2.61 µM, respectively. Analog 4p, 6,6'-bis(3,4-dimethoxycinnamoyl)-α,α-D-trehalose, was as potent as brartemicin against invasion of murine colon 26-L5 carcinoma cells in vitro. The structure-activity relationships of these novel trehalose-based compounds were summarized.

Antitumor anthraquinones from an endophytic actinomycete Micromonospora lupini sp. nov.

Two novel anthraquinones, lupinacidins A (1) and B (2), have been isolated from the culture broth of a new endophytic actinomycete belonging to the genus Micromonospora. Lupinacidins were found to show significant inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells without inhibiting cell growth.