Tachykinin antagonists screening from microbial origin.
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Animals↗
Biomedical subjects
M Okuhara
Publications and source records attributed to M Okuhara.
New antitumor substances, FR901463, FR901464 and FR901465. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.
New antitumor substances, FR901463, FR901464 and FR901465 were isolated from the culture broth of a bacterium of Pseudomonas sp. No.2663. FR901463, FR901464 and FR901465 remarkably enhanced the transcriptional activity of the promoter of SV40 DNA virus. Further, these compounds exhibited potent antitumor activities against murine and human tumor cell lines in vitro.
Animals↗
New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action.
FR901463, FR901464 and FR901465, novel antitumor substances, were isolated from the fermentation broth of Pseudomonas sp. No. 2663. Their antitumor activities were examined in three mouse tumor systems and one human tumor system. The three FR compounds prolonged the life of mice bearing murine ascitic tumor P388 leukemia (T/C values were 160%, 145% and 127% for FR901463, FR901464 and FR901465, respectively), and inhibited the growth of a human solid tumor, A549 lung adenocarcinoma, with different effective dose ranges. FR901464 exhibited most prominent effects on these tumor systems among the three FR compounds. FR901464 also inhibited the growth of murine solid tumors, Colon 38 carcinoma and Meth A fibrosarcoma. To address the involvement of transcriptional activation ability of the three FR compounds in the antitumor effect, we selected FR901464 as a candidate compound and investigated cell cycle transition, chromatin status and endogenous gene expression in FR901464-treated tumor cells having elevated transcriptional activity. FR901464 induced characteristic G1 and G2/M phase arrest in the cell cycle and internucleosomal degradation of genomic DNA with the same kinetics as activation of SV40 promoter-dependent cellular transcription in M-8 tumor cells. In contrast to the potent activation of the viral promoter, FR901464 suppressed the transcription of some inducible endogenous genes but not house keeping genes in M-8 cells. These results suggest that FR901464 may induce a dynamic change of chromatin structure, giving rise to strong antitumor activity, and therefore may represent a new type of drug for cancer chemotherapy.
Animals↗
FR901483, a novel immunosuppressant isolated from Cladobotryum sp. No. 11231. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities.
FR901483, a novel immunosuppressant, has been isolated from the fermentation broth of Cladobotryum sp. No. 11231. The molecular formula of FR901483 has been determined as C20H31N2O6P. FR901483 exerts a potent immunosuppressive activity in vitro and significantly prolongs graft survival time in the rat skin allograft model. This compound has an intriguing tricyclic structure possessing a phosphate ester in its molecule. The ester residue may play an important role in exerting immunosuppressive activity because the desphosphoryl compound is devoid of activity. It is thought that the primary target of immunosuppression by this compound is inhibition of purine nucleotide biosynthesis.
Animals↗
Effect of FR133605, a novel cytokine suppressive agent, on bone and cartilage destruction in adjuvant arthritic rats.
OBJECTIVE: We evaluated the effect of FR133605, a novel inhibitor of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), on bone and cartilage destruction in adjuvant arthritic rats and compared it to corticosteroid, nonsteroidal antiinflammatory drugs (NSAID), and disease modifying antirheumatic drugs (DMARD). METHODS: The antiinflammatory responses were evaluated by measurement of hind paw swelling, body weight, femoral bone mineral density, and glycosaminoglycan content (GAG) in femoral condyles in adjuvant arthritic rats. RESULTS: FR133605 inhibited IL-1 and TNF-alpha production stimulated with lipopolysaccharide (LPS) in human monocytes. FR133605 also inhibited serum IL-1 and TNF-alpha concentrations in LPS treated mice. In contrast, among comparison antirheumatic drugs, only corticosteroid inhibited production at nontoxic concentrations. In adjuvant arthritis, FR133605 significantly inhibited paw swelling, bone and cartilage destruction, and increased body weight. On the other hand, indomethacin significantly inhibited paw swelling, but not bone and cartilage loss. Dexamethasone completely inhibited paw swelling and bone loss, but augmented cartilage breakdown. DMARD weakly restored the loss of GAG contents in articular cartilage. CONCLUSIONS: FR133605 improved bone loss and articular cartilage destruction in adjuvant arthritic rats and the inhibitory effect was closely correlated with the suppressive activity of IL-1 and TNF-alpha production.
Adrenal Cortex Hormones↗
Mechanism of cell detachment from temperature-modulated, hydrophilic-hydrophobic polymer surfaces.
Poly(N-isopropylacrylamide) (PIPAAm), exhibiting a lower critical solution temperature (LCST) at 25 degrees C in physiological phosphate buffered saline solution (pH 7.4) and at 32 degrees C in pure water, was grafted onto the surfaces of commercial polystyrene cell culture dishes. This PIPAAm-grafted surface exhibited hydrophobic surface properties at temperatures over the LCST and hydrophilic surface properties below the LCST. Endothelial cells and hepatocytes attached and proliferated on PIPAAm-grafted surfaces at 37 degrees C, above the LCST. The cultured cells were readily detached from these surfaces by lowering the incubation temperature without the usual damage associated with trypsinization. In this case, the optimum temperature for cell detachment was 10 degrees C for hepatocytes and 20 degrees C for endothelial cells. Cell detachment was partially inhibited by sodium azide treatment, suggesting that cell metabolism directly affects cell detachment. Morphological changes of the adherent cells during cell detachment experiments indicated further involvement of active cellular metabolic processes. Cells detached from hydrophobic-hydrophilic PIPAAm surfaces not only via reduced cell-surface interactions caused by the spontaneous hydration of grafted PIPAAm chains, but also by active cell morphological changes which were a function of cell metabolism.
Acrylic Resins↗
FK143, a novel nonsteroidal inhibitor of steroid 5 alpha-reductase: (1) In vitro effects on human and animal prostatic enzymes.
Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men. We studied in vitro effects of FK143, a nonsteroidal new compound, on 5 alpha-reductase in human and animal prostates. Prostates were obtained from Wistar rats, Beagle dogs, and Cynomolgus monkeys as well as prostatic tissue from BPH patients obtained by the prostatectomy. Nuclear membrane fraction of prostates showed pH dependent 5 alpha-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 of 1.9 nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncompetitive fashion while finasteride, a steroidal 5 alpha-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5 alpha-reductase is constant at pH 5 and 6.5. No inhibitory effects were shown to other oxidoreductases. These results indicate that FK143 is a new type of potent and selective 5 alpha-reductase inhibitor.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
FK143, a novel nonsteroidal inhibitor of steroid 5 alpha-reductase: (2) In vivo effects on rat and dog prostates.
FK143 is a nonsteroidal new inhibitor of steroid 5 alpha-reductase, an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT). We studied in vivo effects of FK143 on rat and dog prostates. FK143 was orally administered to mature male rats for 14 days. At doses above 1 mg/kg, FK143 significantly reduced the wet weights of the ventral prostate and seminal vesicle, but showed no effects on those of the epididymis, testis, and adrenal. Growth of ventral prostate and seminal vesicle was induced by the subcutaneous injection of testosterone propionate (TP) in the castrated young rats and was reduced by FK143 administration at doses above 3.2 mg/kg, while growth induced by 5 alpha-dihydrotestosterone propionate (DHTP) was not affected. FK143 had no binding affinity for the rat androgen receptor. FK143 showed neither estrogenic and antiestrogenic effects on the rat uterus nor androgenic effect on the rat prostate. Concentration of testosterone and DHT in the rat and dog prostates were measured by GC-MS, and administration of 10 mg/kg of FK143 significantly reduced the intraprostatic concentration of DHT. These results indicate that FK143 reduced the prostate growth by inhibiting 5 alpha-reductase activities in the prostates.
5-alpha Reductase Inhibitors↗
WS75624 A and B, new endothelin converting enzyme inhibitors isolated from Saccharothrix sp. No. 75624. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.
Novel endothelin converting enzyme (ECE) inhibitors, WS75624 A and B, have been isolated from the fermentation broth of Saccharothrix sp. No. 75624. These inhibitors were purified from an acetone extract of whole culture broth followed by HP-20 column chromatography, silica gel column chromatography and HPLC. WS75624 A and B showed highly potent ECE inhibitory activity, and both had IC50 values of 0.03 microgram/ml. WS75624 A and B also showed other metalloprotease (collagenase and neutral endopeptidase) inhibitory activity with IC50 values of 1 microgram/ml. Since large amount of WS75624 B was isolated, we tried in vivo evaluation using WS75624 B. WS75624 B inhibited big endothelin-induced pressor effect when administered to SD rat intravenously with big ET-1.
Animals↗
WS75624 A and B, new endothelin converting enzyme inhibitors isolated from Saccharothrix sp. No. 75624. II. Structure elucidation of WS75624 A and B.
The structures of WS75624 A and B, novel endothelin converting enzyme inhibitors, were determined to be 1 and 2A, respectively, by a combination of chemical evidence and a series of 2D NMR spectral analyses.
Aspartic Acid Endopeptidases↗
Biological and pharmacological properties of highly selective new endothelin converting enzyme inhibitor WS79089B isolated from Streptosporangium roseum No. 79089.
WS79089B a highly specific endothelin converting enzyme (ECE) inhibitor has been isolated from the fermentation broth of Streptosporangium roseum No. 79089. WS79089B showed highly selective ECE inhibition activity with IC50 value of 0.14 microM and behaved as a competitive inhibitor of ECE, with Ki values of 8.9 x 10(-8) M. The sodium salt of WS79089B (FR901533) inhibited big endothelin-1 (big ET-1) induced pressor effect in a dose dependent manner when administered to male Sprague-Dawley rats intravenously dosed 2 minutes prior to big ET-1 challenge.
Actinomycetales↗
A new assay method for immunosuppressants with a tacrolimus (FK506)-like mode of action.
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Antifungal Agents↗
A new aromatase inhibitor, FR901537. I. Taxonomy, fermentation, isolation, physiochemical characteristics and biological activities.
FR901537 is a new aromatase inhibitor produced by a bacterium Bacillus sp. No. 3072. Structural studies of FR901537 suggested that it was a novel naphthol derivative having pantetheine in its structure. FR901537 showed a potent inhibitory activity against aromatase from human placenta or rat ovary, but did not inhibit the activity of 11 beta-hydroxylase from bovine adrenal cortex. Lineweaver-Burk plot analysis revealed that FR901537 is a competitive inhibitor.
Animals↗
Novel steroid 5 alpha-reductase inhibitor FK143: its dual inhibition against the two isozymes and its effect on transcription of the isozyme genes.
Recent cloning of the cDNAs for the two isozymes of steroid 5 alpha-reductase (EC 1.3.99.5) allowed individual expression of the isozymes and permitted us to investigate the action of steroid 5 alpha-reductase inhibitors against the individual isozymes without any ambiguity that may be caused by coexistence of the isozymes in tissue preparations. We examined the kinetic characteristics of FK143 (4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1- yl]butyric acid), a novel nonsteroidal steroid 5 alpha-reductase inhibitor against cloned human and rat steroid 5 alpha-reductase isozymes. FK143 was shown to inhibit both isozymes equally. The mode of the inhibition of FK143 against both isozymes was noncompetitive. The inhibition constants Kie and Kies of FK143 for human types 1 and 2 were 27.0 and 19.6 nM and 19.9 and 14.5 nM, respectively. Species selectivity between human and rat of the inhibitory activity of FK143 against both isozymes was not found. We also examined the effect of FK143 on the in vivo expression of the genes encoding for the rat steroid 5 alpha-reductase isozymes. FK143 reduced the testosterone-induced increase in the amount of the type 1 mRNA in castrated rat, whereas it did not substantially affect the amount of the type 2 mRNA.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Subtype- and species-selectivity of a tachykinin receptor antagonist, FK888, for cloned rat and human tachykinin receptors.
We investigated the receptor-binding properties and potencies of FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N- phenylmethyl-3-(2-naphthyl)-L-alaninamide), a tachykinin receptor antagonist, for the rat and human tachykinin receptor subtypes (NK1, NK2 and NK3) expressed in transfected mammalian cells. In displacement analyses, using membrane preparations derived from monkey kidney COS-7 cells transiently expressing tachykinin receptor subtypes, FK888 showed a subtype selectivity for NK1 receptor and its affinity for the human NK1 receptor was 320-fold higher than that for the rat NK1 receptor, demonstrating species difference in its binding affinity. This was in marked contrast to FK224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L- allothreonyl]-L-asparaginyl]-L-serine-n-lactone) that was selective for NK1 and NK2 receptors with similar affinities for the rat and human receptors. In Chinese hamster ovary cells permanently expressing the human NK1 receptor, FK888 inhibited the substance P-induced phosphatidylinositol hydrolysis and produced a parallel shift in the dose-response curve for substance P. Schild analysis of the antagonism of phosphatidylinositol hydrolysis by FK888 yielded a pA2 value of 8.9 and a slope of 0.97 of the regression line. FK888 itself showed no stimulatory effect on phosphatidylinositol hydrolysis in Chinese hamster ovary cells expressing the human NK1 receptor. Thus, FK888 is a potent, competitive and selective antagonist for human NK1 receptor.
Animals↗
Immunomodulators.
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Adjuvants, Immunologic↗
Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells.
FR901228, a novel antitumor antibiotic, reversed the transformed morphology of the Ha-ras transformants, Ras-1 cells, and inhibited their growth. The reduction of c-myc expression was observed in FR901228-treated Ras-1 cells by RNA dot-blot hybridization. This reduction of c-myc expression and morphological reversion of the transformed cells to normal were correlated with growth inhibition (G0/G1 arrest in cell cycle).
3T3 Cells↗
WF11899A, B and C, novel antifungal lipopeptides. I. Taxonomy, fermentation, isolation and physico-chemical properties.
WF11899A, B and C, novel antifungal lipopeptide antibiotics were isolated from the culture broth of Coleophoma empetri F-11899. These compounds belong to the echinocandin type of lipopeptides. Of these compounds, WF11899A showed good solubility in water. These three antibiotics possess potent in vitro antifungal activities against Candida spp.
Animals↗