In vitro and in vivo antimicrobial activity of TS2037, a novel aminoglycoside antibiotic.

To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC and MIC of TS2037 against clinical isolates of MRSA (n = 54) were both 0.

Intervenolin, a new antitumor compound with anti-Helicobacter pylori activity, from Nocardia sp. ML96-86F2.

Because stromal cells can regulate the growth and metastasis of tumor cells, a compound that modulates the interaction between the stromal cells and the tumor cells can control the tumor progression. In the course of our screening for such a compound, we have isolated a new compound, intervenolin, from the culture broth of Nocardia sp. ML96-86F2.

In vivo imaging of proteasome inhibition using a proteasome-sensitive fluorescent reporter.

A proteasome degrades numerous regulatory proteins that are critical for tumor growth and is therefore recognized as a promising anticancer target. Determining proteasome activity in the tumors of mice bearing xenografts is essential for the development of novel proteasome inhibitors. We developed a system for in vivo imaging of proteasome inhibition in the tumors of living mice, using a proteasome-sensitive fluorescent reporter, ZsProSensor-1.

Increased ABCB1 expression in TP-110-resistant RPMI-8226 cells.

TP-110, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/TP-110) cells and elucidated their resistance mechanisms. The IC₅₀ value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells.

Structure-activity relationship of boronic acid derivatives of tyropeptin: proteasome inhibitors.

The structure-activity relationship of the boronic acid derivatives of tyropeptin, a proteasome inhibitor, was studied. Based on the structure of a previously reported boronate analog of tyropeptin (2), 41 derivatives, which have varying substructure at the N-terminal acyl moiety and P2 position, were synthesized. Among them, 3-phenoxyphenylacetamide 6 and 3-fluoro picolinamide 22 displayed the most potent inhibitory activity toward chymotryptic activity of proteasome and cytotoxicity, respectively.

NBRI16716A, a new antitumor compound against human prostate cancer cells, produced by Perisporiopsis melioloides Mer-f16716.

Prostate stroma can regulate the growth and metastasis of prostate cancer through the tumor-stromal cell interactions. Thus, small molecules that modulate the tumor-stromal cell interactions will have a chance to become new antitumor drugs. In the course of our screening of the modulators, we isolated three new natural compounds, NBRI16716A (1), NBRI16716B (2) and NBRI16716C (3), from the fermentation broth of Perisporiopsis melioloides Mer-f16716, although compound 2 was already reported as a chemical degradation product of isotriornicin.

NBRI17671, a new antitumor compound, produced by Acremonium sp. CR17671.

The interaction between the receptor for advanced glycation end-product (RAGE) and amphoterin has an important role in tumor growth and metastasis. Because the abrogation of the interaction results in the inhibition of the tumor growth and metastasis, we designed a screening system for an inhibitor of the interaction between RAGE and amphoterin. In the course of our screening of the inhibitor, we isolated a novel natural compound NBRI17671 (1) from the fermentation broth of Acremonium sp.

Mitochondrial inhibitors show preferential cytotoxicity to human pancreatic cancer PANC-1 cells under glucose-deprived conditions.

Large areas of tumor are nutrient-starved and hypoxic due to a disorganized vascular system. Therefore, we screened small molecules to identify cytotoxic agents that function preferentially in nutrient-starved conditions. We found that efrapeptin F had preferential cytotoxicity to nutrient-deprived cells compared with nutrient-sufficient cells.

Rubratoxin A specifically and potently inhibits protein phosphatase 2A and suppresses cancer metastasis.

Although cytostatin analog protein phosphatase 2A (PP2A)-specific inhibitors are promising candidates of a new type of anticancer drug, their development has been hindered because of their liability. To find new classes of PP2A-specific inhibitors, we conducted a screening with microbial metabolites and found that rubratoxin A, a classical mycotoxin, is a highly specific and potent inhibitor of the enzyme. While rubratoxin A inhibits PP2A at Ki = 28.

Leucinostatin A inhibits prostate cancer growth through reduction of insulin-like growth factor-I expression in prostate stromal cells.

Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture system, in which the growth of human prostate cancer DU-145 cells is stimulated by prostate stromal cells (PrSC) through insulin-like growth factor I (IGF-I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor-stromal cell interactions.

TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells.

TP-110, a new proteasome inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226.

Synthesis of boronic acid derivatives of tyropeptin: proteasome inhibitors.

Boronic acid derivatives of tyropeptin were synthesized with TP-110 as the lead compound. Due to the lability of the aminoboronic acid moiety, careful design of the deprotection and coupling sequence was required. Liquid-liquid partition chromatography was found to be a powerful tool for purification of compounds of this class.

New atpenins, NBRI23477 A and B, inhibit the growth of human prostate cancer cells.

The growth and metastasis of prostate cancer are regulated by prostate stroma through the tumor-stromal cell interactions. Small molecules that modulate the tumor-stromal cell interactions will be new anticancer drugs. In the course of our screening of the modulators, we isolated two new atpenins, NBRI23477 A (4) and B (5), from the fermentation broth of Penicillium atramentosum PF1420.

Inhibitors of insulin-like growth factor-1 receptor tyrosine kinase are preferentially cytotoxic to nutrient-deprived pancreatic cancer cells.

Chronic deprivation of nutrients is rare in normal tissues, however large areas of tumor are nutrient-starved and hypoxic due to a disorganized vascular system. Some cancers show an inherent ability to tolerate severe growth conditions. Therefore, we screened chemical compounds to identify cytotoxic agents that function preferentially in nutrient-deprived conditions.

Ceramidastin, a novel bacterial ceramidase inhibitor, produced by Penicillium sp. Mer-f17067.

Decrease of ceramide in the skin is one of the aggravating factors of atopic dermatitis. The skin is often infected by ceramidase-producing bacteria, such as Pseudomonas aeruginosa. The bacterial ceramidase then degrades ceramide in the skin.

Phthoxazolin A inhibits prostate cancer growth by modulating tumor-stromal cell interactions.

Because stroma in tumor tissues can promote prostate cancer development, modulation of tumor-stromal cell interactions may represent an attractive new strategy for cancer treatment. Here, we report that phthoxazolin A and its analog inthomycin B inhibit the growth of human prostate cancer DU-145 cells by modulating tumor-stromal cell interactions. Using an in vitro coculture system, in which prostate cancer cell growth is upregulated by prostate stromal cells (PrSC), we found that phthoxazolin A and inthomycin B strongly inhibited the growth of DU-145 cells when in coculture with PrSC compared to DU-145 cells cultured alone.

A new terrein glucoside, a novel inhibitor of angiogenin secretion in tumor angiogenesis.

Angiogenesis is a critical step for the tumor therapy. Many angiogenic factors are involved in the tumor angiogenesis. In the course of our screening for inhibitors of angiogenin secretion, one of angiogenic factors, we have isolated a new terrein glucoside (1) and terrein (2) from the fermentation broth of fungal strain Aspergillus sp.

Transforming growth factor-beta1 modulates tumor-stromal cell interactions of prostate cancer through insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) secreted from the prostate stroma mediates tumor-stromal cell interactions in prostate cancer development. We have recently reported that human prostate stromal cells (PrSC) stimulate human prostate cancer DU-145 cell growth via IGF-I. Transforming growth factor-beta1 (TGF-beta1) also plays a critical role in tumor-stromal cell interactions, but TGF-beta1 has pleiotropic effects as it can modulate growth of prostate cancer either positively or negatively.

Drug-induced readthrough of premature stop codons leads to the stabilization of laminin alpha2 chain mRNA in CMD myotubes.

Background: The most common form of congenital muscular dystrophy is caused by a deficiency in the alpha2 chain of laminin-211, a protein of the extracellular matrix. A wide variety of mutations, including 20 to 30% of nonsense mutations, have been identified in the corresponding gene, LAMA2. A promising approach for the treatment of genetic disorders due to premature termination codons (PTCs) is the use of drugs to force stop codon readthrough.

Effect of varying the 4''-position of arbekacin derivatives on antibacterial activity against MRSA and Pseudomonas aeruginosa.

4''-Deoxy-4''-episubstituted arbekacin derivatives and 4''-epi-5-deoxy-5-episubstituted arbekacin derivatives were designed and synthesized. Arbekacin and 4''-epiarbekacin both displayed the same antibacterial activity against Staphylococcus aureus (including methicillin-resistant S. aureus (MRSA)) and Pseudomonas aeruginosa.

Synthesis and antibacterial activity of 5-deoxy-5-episubstituted arbekacin derivatives.

5-Deoxy-5-episubstituted arbekacin derivatives have been designed and efficiently synthesized. The synthetic compounds showed potent antibacterial activity against both Staphylococcus aureus, including methicillin-resistant S. aureus, and Pseudomonas aeruginosa.

A new proteasome inhibitor, TP-110, induces apoptosis in human prostate cancer PC-3 cells.

Proteasome inhibitors are useful in the treatment of cancer. Recently, we found a new proteasome inhibitor, TP-110, derived from tyropeptin A produced by Kitasatospora sp. Here we report that TP-110 induces apoptosis in human prostate cancer PC-3 cells.