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1.
Bioorg Med Chem Lett ; 106: 129731, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38621594

ABSTRACT

The inhibition of kynurenine production is considered a promising target for cancer immunotherapy. In this study, an amino acid derivative, compound 1 was discovered using a cell-based assay with our screening library. Compound 1 suppressed kynurenine production without inhibiting indoleamine 2,3-dioxygenase 1 (IDO1) activity. The activity of 1 was derived from the inhibition of IDO1 by a metabolite of 1, O-benzylhydroxylamine (OBHA, 2a). A series of N-substituted 2a derivatives that exhibit potent activity in cell-based assays may represent effective prodrugs. Therefore, we synthesized and evaluated novel N,O-substituted hydroxylamine derivatives. The structure-activity relationships revealed that N,O-substituted hydroxylamine 2c inhibits kynurenine production in a cell-based assay. We conducted an in vivo experiment with 2c, although the effectiveness of O-substituted hydroxylamine derivatives in vivo has not been previously reported. The results indicate that N,O-substituted hydroxylamine derivatives are promising IDO1 inhibitors.


Subject(s)
Hydroxylamine , Indoleamine-Pyrrole 2,3,-Dioxygenase , Kynurenine , Kynurenine/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Structure-Activity Relationship , Humans , Hydroxylamine/chemistry , Hydroxylamine/pharmacology , Hydroxylamines/chemistry , Hydroxylamines/pharmacology , Molecular Structure , Animals , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Dose-Response Relationship, Drug
2.
Nat Commun ; 13(1): 4063, 2022 07 13.
Article in English | MEDLINE | ID: mdl-35831322

ABSTRACT

Point-mutations of MEK1, a central component of ERK signaling, are present in cancer and RASopathies, but their precise biological effects remain obscure. Here, we report a mutant MEK1 structure that uncovers the mechanisms underlying abnormal activities of cancer- and RASopathy-associated MEK1 mutants. These two classes of MEK1 mutations differentially impact on spatiotemporal dynamics of ERK signaling, cellular transcriptional programs, gene expression profiles, and consequent biological outcomes. By making use of such distinct characteristics of the MEK1 mutants, we identified cancer- and RASopathy-signature genes that may serve as diagnostic markers or therapeutic targets for these diseases. In particular, two AKT-inhibitor molecules, PHLDA1 and 2, are simultaneously upregulated by oncogenic ERK signaling, and mediate cancer-specific ERK-AKT crosstalk. The combined expression of PHLDA1/2 is critical to confer resistance to ERK pathway-targeted therapeutics on cancer cells. Finally, we propose a therapeutic strategy to overcome this drug resistance. Our data provide vital insights into the etiology, diagnosis, and therapeutic strategy of cancers and RASopathies.


Subject(s)
Neoplasms , Proto-Oncogene Proteins c-akt , Humans , MAP Kinase Kinase 1/genetics , MAP Kinase Signaling System/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/genetics
3.
Parasitol Int ; 81: 102267, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33307212

ABSTRACT

Metacytofilin (MCF) was isolated from the fungus Metarhizium sp. TA2759. Although MCF possesses anti-Toxoplasma activity, the effects of this compound against other parasites are unknown. Here, we evaluated the in vitro anti-malarial activity of MCF against the 3D7 strain and the chloroquine-resistant K1 strain of Plasmodium falciparum. The half maximal inhibitory concentrations (IC50) of MCF against the 3D7 and K-1 strains following culture for 48 h were 666 nM and 605 nM, respectively. Artemisinin was more potent than MCF against both strains (3D7 IC50: 17.4 nM; K-1 IC50: 18.3 nM), while chloroquine was ineffective against the chloroquine-resistant strain (3D7 IC50: 39.1 nM; K-1 IC50: 1.62 µM). MCF affected the ring stage of the parasites, resulting in their death as shown by spots within red blood cells. MCF also inhibited parasite growth following culture for 72 h (3D7 IC50, 285 nM). Four optical isomers of cyclo[Leu-Phe]-diketopiperazine derivatives with modified methoxy and/or hydroxyl groups lost anti-malarial activity, suggesting that the spatial positions of the methoxy and hydroxyl groups in MCF play an important role in its anti-malarial effects. Together, these data suggest that MCF may represent a promising lead compound for treatment of drug-resistant malarial parasites.


Subject(s)
Antimalarials/pharmacology , Oxazines/pharmacology , Plasmodium falciparum/drug effects
4.
J Infect Dis ; 221(5): 766-774, 2020 02 18.
Article in English | MEDLINE | ID: mdl-31573038

ABSTRACT

BACKGROUND: Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound. METHODS: Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. RESULTS: In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. CONCLUSIONS: With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.


Subject(s)
Antiparasitic Agents/therapeutic use , Infectious Disease Transmission, Vertical/prevention & control , Oxazines/therapeutic use , Toxoplasma/drug effects , Toxoplasmosis/drug therapy , Toxoplasmosis/mortality , Administration, Intravenous , Administration, Oral , Animals , Antiparasitic Agents/administration & dosage , Antiparasitic Agents/pharmacology , DNA Replication/drug effects , DNA, Protozoan , Disease Models, Animal , Female , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Oxazines/administration & dosage , Oxazines/pharmacology , Pregnancy , Survival Rate , Toxoplasma/genetics , Toxoplasmosis/parasitology , Toxoplasmosis/transmission , Treatment Outcome
5.
J Antibiot (Tokyo) ; 73(3): 167-170, 2020 03.
Article in English | MEDLINE | ID: mdl-31735911

ABSTRACT

Small cell lung cancer (SCLC) is a severe malignancy with early and widespread metastasis, and novel therapeutic drugs are needed. To identify cytotoxic natural compounds against SCLC, we screened libraries of microbial fermentation broths using several lung cancer cell lines. We found that the actinomycete strain MG372-hF19 produces a compound that has not been isolated from natural sources but previously chemically synthesized, 6-chloro-1H-indole-3-carboxaldehyde (1), and an entirely new compound, named 6-deoxy-α-L-talopyranose 1-(6-chloro-1H-indole-3-carboxylate) (2), together with leptomycins. The molecular formulas of the compounds were established as C9H6ClNO and C15H16ClNO6, respectively, via high-resolution electrospray ionization mass spectrometry, and their structures were determined using detailed NMR. Absolute configurational analysis of the sugar unit of compound 2 revealed that the compound incorporates the rare deoxyhexose 6-deoxy-α-L-talopyranose. Both compounds exhibited weak growth-inhibiting activities against human lung cancer cell lines.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Glycosides/chemistry , Streptomycetaceae/metabolism , Antineoplastic Agents/metabolism , Cell Line, Tumor , Humans , Small Cell Lung Carcinoma/drug therapy
6.
J Nat Prod ; 82(5): 1120-1127, 2019 05 24.
Article in English | MEDLINE | ID: mdl-31017786

ABSTRACT

Leucinostatin Y, a new peptaibiotic, was isolated from the culture broth of the entomoparasitic fungus Purpureocillium lilacinum 40-H-28. The planar structure was elucidated by detailed analysis of its NMR and MS/MS data. The absolute configurations of the amino acids were partially determined by an advanced Marfey's method. The biological activities of leucinostatin Y were assessed using human pancreatic cancer cells, revealing the importance of the C-terminus of leucinostatins for preferential cytotoxicity to cancer cells under glucose-deprived conditions and inhibition of mitochondrial function.


Subject(s)
Antineoplastic Agents/isolation & purification , Paecilomyces/chemistry , Peptaibols/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Magnetic Resonance Spectroscopy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Peptaibols/chemistry , Peptaibols/pharmacology
7.
J Antibiot (Tokyo) ; 70(12): 1146-1149, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29066793

ABSTRACT

Osteoblast and adipocyte are differentiated from mesenchymal stem cells and dysregulation of the differentiation might result in disease, such as osteoporosis and diabetes. To find small compounds that induce osteoblast differentiation, we screened an in-house natural compounds library with mouse preosteoblastic MC3T3-E1 cells using alkaline phosphatase (ALP) expression as an early osteoblast marker. We found that phenazine-1-carboxylic acid (PCA), one of the major phenazine derivatives produced by Pseudomonas, induced osteoblast differentiation in the cells at micromolar concentrations. PCA acted synergistically with an agonist of hedgehog signaling in inducing ALP activity in the cells. We also found that 2-hydroxy-PCA (2H-PCA) induced osteoblast differentiation in the cells but 2-methoxy-PCA and 1-hydroxy-phenazine did not. Unexpectedly, treatment of mouse pluripotent mesenchymal C3H10T1/2 cells with PCA or 2H-PCA induced an obvious morphological change. Oil Red O staining and real-time reverse-transcription PCR analysis revealed that PCA induced not osteoblast differentiation but adipocyte differentiation in C3H10T1/2 cells. These compounds could allow us to investigate the mechanism of osteoblast and adipocyte differentiation in the two model cell systems through a chemical biology approach.


Subject(s)
Adipocytes/cytology , Adipogenesis/drug effects , Mesenchymal Stem Cells/cytology , Osteoblasts/cytology , Osteogenesis/drug effects , 3T3 Cells , Alkaline Phosphatase/biosynthesis , Animals , Cell Line , Mice , Phenazines/pharmacology , Pseudomonas/metabolism
8.
J Antibiot (Tokyo) ; 2017 Sep 06.
Article in English | MEDLINE | ID: mdl-28874847

ABSTRACT

Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK. We performed a screening to discover new MEK inhibitors, and found a guanine derivative produced by Streptomyces sp. MK63-43F2. This guanine derivative was identified to be 2-amino-4-methoxy-5-cyanopyrrolo[2,3-d]pyrimidine (1) through spectroscopic analysis. Compound 1 inhibited MEK1 kinase activity in an ATP-dependent manner and suppressed the phosphorylation of ERK in cancer cells and cell proliferation. Therefore, 1 might be a potent lead compound for new MEK inhibitors.The Journal of Antibiotics advance online publication, 6 September 2017; doi:10.1038/ja.2017.100.

10.
J Nat Prod ; 78(2): 188-95, 2015 Feb 27.
Article in English | MEDLINE | ID: mdl-25611347

ABSTRACT

Quinofuracins A-E, novel anthraquinone derivatives containing ß-D-galactofuranose that were isolated from the fungus Staphylotrichum boninense PF1444, induced p53-dependent cell death in human tumor cells. The structures of quinofuracins A-E, including absolute configurations, were elucidated by extensive spectroscopic analysis and chemical transformation studies. Quinofuracins were classified into three groups according to the aglycone moieties. 5'-Oxoaverantin was present in quinofuracins A-C, whereas averantin and versicolorin B were identified in quinofuracins D and E, respectively. These quinofuracins induced p53-dependent growth suppression in human glioblastoma LNZTA3 cells.


Subject(s)
Anthraquinones/isolation & purification , Anthraquinones/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Ascomycota/chemistry , Tumor Suppressor Protein p53/metabolism , Anthraquinones/chemistry , Antineoplastic Agents/chemistry , Cell Death/drug effects , Drug Screening Assays, Antitumor , Glioblastoma/drug therapy , Humans , Japan , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Tumor Suppressor Protein p53/drug effects
11.
Biosci Biotechnol Biochem ; 74(9): 1913-9, 2010.
Article in English | MEDLINE | ID: mdl-20834157

ABSTRACT

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. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Drug Resistance, Neoplasm , Multiple Myeloma/drug therapy , Oligopeptides/pharmacology , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Inhibitory Concentration 50 , Multiple Myeloma/chemistry , Multiple Myeloma/metabolism , Proteasome Inhibitors , Tumor Cells, Cultured , Verapamil/pharmacology
12.
Anticancer Res ; 29(4): 977-85, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19414335

ABSTRACT

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. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another proteasome inhibitor, MG-132. These results indicate that proteasome inhibitors reduce the level of IAPs and that the apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated apoptosis. Taken together, the alteration of the apoptosis regulatory proteins by a proteasome inhibitor induces apoptosis in tumor cells.


Subject(s)
Apoptosis/drug effects , Inhibitor of Apoptosis Proteins/metabolism , Multiple Myeloma/drug therapy , Oligopeptides/pharmacology , Proteasome Inhibitors , Caspases/metabolism , Cytochromes c/metabolism , Down-Regulation , Humans , Immunoblotting , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Poly(ADP-ribose) Polymerases/metabolism , Tumor Cells, Cultured
13.
Biosci Biotechnol Biochem ; 71(4): 1036-43, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17420589

ABSTRACT

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. TP-110 showed strong cytotoxicity to PC-3 cells (IC(50)=0.05 muM). It increased the number of cells in the G(2)-M phase and increased the accumulated amounts of the p21 and p27 proteins, which are negative regulators of cell cycle progression. Furthermore, it induced apoptosis along with chromatin condensation and DNA fragmentation in PC-3 cells, and TP-110-induced apoptosis appeared to be associated with caspase activation. Additionally, TP-110 inhibited not only the degradation of IkappaB and the nuclear translocation of nuclear factor-kappaB (NF-kappaB), but also the DNA binding activity of NF-kappaB. These results indicate that TP-110 shows a strong growth inhibition and apoptosis in PC-3 cells.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Apoptosis/drug effects , Oligopeptides/pharmacology , Prostatic Neoplasms/drug therapy , Proteasome Inhibitors , Benzimidazoles , Blotting, Western , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Fragmentation/drug effects , Fluorescent Dyes , Humans , Male , NF-kappa B/biosynthesis , NF-kappa B/genetics , Reverse Transcriptase Polymerase Chain Reaction
14.
J Antibiot (Tokyo) ; 59(4): 215-9, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16830888

ABSTRACT

Kigamicin D did not show any immunosuppressive activity in mixed lymphocyte culture reaction and mitogen induced lymphocyte blastogenesis in vitro and graft versus host reaction in vivo. Natural killer cell activity in spleen cells was not affected by oral administration of kigamicin D. Instead, delayed-type hypersensitivity response to sheep red blood cells was stimulated at a broad dosage level. It is concluded that kigamicin D increases cellular immunity to specific antigen.


Subject(s)
Doxorubicin/analogs & derivatives , Immunity, Cellular/drug effects , Oxazoles/pharmacology , Animals , Cells, Cultured , Doxorubicin/pharmacology , Graft vs Host Reaction/drug effects , Hypersensitivity, Delayed , Killer Cells, Natural/drug effects , Lymphocyte Activation/drug effects , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C3H , Models, Animal , Spleen/immunology
15.
Biosci Biotechnol Biochem ; 69(9): 1733-42, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16195592

ABSTRACT

Tyropeptin A, a potent proteasome inhibitor, was isolated from the culture broth of Kitasatospora sp. MK993-dF2. We synthesized the derivatives of tyropeptin A to enhance its inhibitory potency. Among the synthesized derivatives, the most potent compound, TP-104, exhibited a 20-fold inhibitory potency enhancement for chymotrypsin-like activity of 20S proteasome compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the post-glutamyl-peptide hydrolyzing (PGPH) and the trypsin-like activities of 20S proteasome. In vitro TP-110 strongly inhibited the growth of various cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Dipeptides/chemistry , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Proteasome Inhibitors , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Chymotrypsin/antagonists & inhibitors , Chymotrypsin/chemistry , Dipeptides/pharmacology , Drug Screening Assays, Antitumor , Humans , Proteasome Endopeptidase Complex/chemistry
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