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1.
Org Biomol Chem ; 21(30): 6129-6133, 2023 Aug 02.
Article in English | MEDLINE | ID: mdl-37477410

ABSTRACT

The concise syntheses of (-)-habiterpenol and (+)-2,3-epi-habiterpenol from (3aR)-(+)-sclareolide and 6-methoxyindanone in 11 and 12 steps, respectively, were enabled by the regioselective addition of the TMS-indenyl anion and the facile stereoselective metal hydride hydrogen atom transfer (MHAT)-initiated redox radical cyclization of alkenylsilane.

2.
Yakugaku Zasshi ; 142(10): 1067-1075, 2022.
Article in Japanese | MEDLINE | ID: mdl-36184441

ABSTRACT

Research on natural product chemistry via organic chemistry ranges from isolation and structural elucidation to total synthesis, drug discovery, and chemical biology. Discoveries in organic chemistry, such as novel reactions and synthetic strategies, are enabled by the studies of total synthesis. Thus, organic (synthetic) chemistry and natural product chemistry are correlated. We conducted comprehensive studies, including structure-activity relationship, drug discovery, and total synthesis studies, on the synthetic organic chemistry of natural products with unique biological activities and the development of novel reactions discovered through these products. This review describes the total synthesis of simpotentin, a novel potentiator of amphotericin B, and the development of the novel lactonization reactions of homopropargyl alcohols via intramolecular ketene trapping.


Subject(s)
Biological Products , Alcohols , Amphotericin B , Biological Products/chemistry , Chemistry, Organic , Drug Discovery
3.
Chem Pharm Bull (Tokyo) ; 70(4): 261-268, 2022.
Article in English | MEDLINE | ID: mdl-35370202

ABSTRACT

Habiterpenol is a G2 checkpoint inhibitor isolated from the culture broth of Phytohabitans sp. 3787_5. Here, we report the synthesis of new habiterpenol analogs through the total synthesis process of habiterpenol and evaluating the analogs for G2 checkpoint inhibitory activity. We investigated two different synthetic approaches for total synthesis, with intramolecular conjugate addition and Ti(III)-mediated radical cyclization as key reactions. Although the former was unsuccessful, the latter reaction facilitated stereoselective total synthesis and determination of the absolute configuration of habiterpenol. The extension of these chemistries to a structure-activity relationship (SAR) study gave new habiterpenol analogs, which could not be derived from natural habiterpenol and only be synthesized by applying the total synthesis. Therefore, this study provides important insights into SAR studies of habiterpenol.


Subject(s)
Triterpenes , Cyclization , Stereoisomerism , Structure-Activity Relationship , Triterpenes/pharmacology
4.
J Pharm Health Care Sci ; 7(1): 18, 2021 May 04.
Article in English | MEDLINE | ID: mdl-33941283

ABSTRACT

BACKGROUND: In clinical practice, a mixed suspension of clopidogrel bisulfate and magnesium oxide (MgO) tablets is administered frequently via a feeding tube. However, there is no report on the changes occurring when suspensions of these two drugs are combined, including the effects or potential decrease in dose following tube administration. Thus, the purpose of our study was to investigate the (i) changes caused by mixing clopidogrel bisulfate (ion form) and MgO tablets and (ii) effects on the administered clopidogrel dose after passing through a feeding tube. METHODS: The molecular structure of clopidogrel generated in a mixture of clopidogrel bisulfate and a basic compound, such as sodium bicarbonate or MgO tablet, was determined by 1H-NMR after extraction and purification. The suspension of clopidogrel bisulfate tablet alone and the mixed suspension of clopidogrel bisulfate tablet and MgO tablet were passed through a feeding tube. We compared the yield of the molecular form of clopidogrel from each passed fraction. RESULTS: The substance obtained from the mixture of clopidogrel bisulfate tablet and sodium bicarbonate or MgO tablet was identified as the molecular form of clopidogrel, and chemical degradation did not occur under these conditions. In the tube passage test, the yield of clopidogrel (molecular form) from the mixture of clopidogrel bisulfate and MgO tablets was lower than that from the suspension of clopidogrel bisulfate tablet alone. CONCLUSIONS: The mixture of clopidogrel bisulfate and MgO tablets caused a considerable reduction in the administered dose passed through the feeding tube. Therefore, it is recommended to administer the suspensions of clopidogrel bisulfate and MgO tablets separately for safe and effective pharmacotherapy.

5.
Org Lett ; 23(7): 2831-2835, 2021 04 02.
Article in English | MEDLINE | ID: mdl-33750143

ABSTRACT

A one-pot γ-lactonization of homopropargyl alcohols via an alkyne deprotonation/boronation/oxidation sequence has been developed. Oxidation of the generated alkynyl boronate affords the corresponding ketene intermediate, which is trapped by the adjacent hydroxy group to furnish the γ-lactone. We have optimized the conditions as well as examined the substrate scope and synthetic applications of this efficient one-pot lactonization.

6.
J Am Chem Soc ; 142(43): 18599-18618, 2020 10 28.
Article in English | MEDLINE | ID: mdl-32991152

ABSTRACT

Here we interrogate the structurally dense (1.64 mcbits/Å3) GABAA receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. 13C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway. Experiment and computation converge on the driving forces behind two surprising observations. First, an oxetane acetal persists in concentrated mineral acid (1.5 M DCl in THF-d8/D2O); its longevity is correlated to destabilizing steric clash between substituents upon ring-opening. Second, a regioselective oxidation of des-hydroxybilobalide is found to rely on lactone acidification through lone-pair delocalization, which leads to extremely rapid intermolecular enolate equilibration. We also establish equivalent effects of (-)-bilobalide and the nonconvulsive sesquiterpene (-)-jiadifenolide on action potential-independent inhibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilobalide distinguishes it from other scaffolds and may characterize natural product (NP) space more generally. Therefore, we also include a Python script to quickly (ca. 132 000 molecules/min) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.


Subject(s)
Cyclopentanes/chemistry , Furans/chemistry , GABA-A Receptor Antagonists/chemical synthesis , Ginkgo biloba/chemistry , Ginkgolides/chemistry , Bromides/chemistry , Cyclopentanes/chemical synthesis , Furans/chemical synthesis , GABA-A Receptor Antagonists/chemistry , Ginkgo biloba/metabolism , Ginkgolides/chemical synthesis , Isotope Labeling , Lactones/chemistry , Molecular Conformation , Oxidation-Reduction , Stereoisomerism
7.
Cancer Chemother Pharmacol ; 85(4): 661-672, 2020 04.
Article in English | MEDLINE | ID: mdl-32072218

ABSTRACT

PURPOSE: We postulate that the deoxyguanosine analogue CNDAG [9-(2-C-cyano-2-deoxy-1-ß-D-arabino-pentofuranosyl)guanine] likely causes a single-strand break after incorporation into DNA, similar to the action of its cytosine congener CNDAC, and that subsequent DNA replication across the unrepaired nick would generate a double-strand break. This study aimed at identifying cellular responses and repair mechanisms for CNDAG prodrugs, 2-amino-9-(2-C-cyano-2-deoxy-1-ß-D-arabino-pentofuranosyl)-6-methoxy purine (6-OMe) and 9-(2-C-cyano-2-deoxy-1-ß-D-arabino-pentofuranosyl)-2,6-diaminopurine (6-NH2). Each compound is a substrate for adenosine deaminase, the action of which generates CNDAG. METHODS: Growth inhibition assay, clonogenic survival assay, immunoblotting, and cytogenetic analyses (chromosomal aberrations and sister chromatid exchanges) were used to investigate the impact of CNDAG on cell lines. RESULTS: The 6-NH2 derivative was selectively potent in T cell malignant cell lines. Both prodrugs caused increased phosphorylation of ATM and its downstream substrates Chk1, Chk2, SMC1, NBS1, and H2AX, indicating activation of ATM-dependent DNA damage response pathways. In contrast, there was no increase in phosphorylation of DNA-PKcs, which participates in repair of double-strand breaks by non-homologous end-joining. Deficiency in ATM, RAD51D, XRCC3, BRCA2, and XPF, but not DNA-PK or p53, conferred significant clonogenic sensitivity to CNDAG or the prodrugs. Moreover, hamster cells lacking XPF acquired remarkably more chromosomal aberrations after incubation for two cell cycle times with CNDAG 6-NH2, compared to the wild type. Furthermore, CNDAG 6-NH2 induced greater levels of sister chromatid exchanges in wild-type cells exposed for two cycles than those for one cycle, consistent with increased double-strand breaks after a second S phase. CONCLUSION: CNDAG-induced double-strand breaks are repaired mainly through homologous recombination.


Subject(s)
Cytarabine/analogs & derivatives , DNA Damage/drug effects , DNA Repair/drug effects , Homologous Recombination/drug effects , Leukemia, T-Cell/drug therapy , Cell Survival , Cytarabine/chemistry , Cytarabine/pharmacology , Humans , Leukemia, T-Cell/pathology , Phosphorylation , Tumor Cells, Cultured
8.
Nature ; 575(7784): 643-646, 2019 11.
Article in English | MEDLINE | ID: mdl-31618759

ABSTRACT

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood1-4. Antagonism of γ-aminobutyric acid A receptors (GABAARs) by bilobalide has been linked to the rescue of cognitive deficits in mouse models of Down syndrome5. A lack of convulsant activity coupled with neuroprotective effects have led some to postulate an alternative, unidentified target4; however, steric congestion and the instability of bilobalide1,2,6 have prevented pull-down of biological targets other than the GABAΑRs. A concise and flexible synthesis of bilobalide would facilitate the development of probes for the identification of potential new targets, analogues with differential selectivity between insect and human GABAΑRs, and stabilized analogues with an enhanced serum half-life7. Here we exploit the unusual reactivity of bilobalide to enable a late-stage deep oxidation that symmetrizes the molecular core and enables oxidation states to be embedded in the starting materials. The same overall strategy may be applicable to G. biloba congeners, including the ginkgolides-some of which are glycine-receptor-selective antagonists8. A chemical synthesis of bilobalide should facilitate the investigation of its biological effects and its therapeutic potential.


Subject(s)
Cyclopentanes/chemical synthesis , Furans/chemical synthesis , Ginkgolides/chemical synthesis , Chemistry Techniques, Analytical , Ginkgo biloba/chemistry , Oxidation-Reduction
9.
Org Lett ; 21(14): 5596-5599, 2019 07 19.
Article in English | MEDLINE | ID: mdl-31246478

ABSTRACT

The total synthesis of simpotentin (1), a new potentiator of amphotericin B activity against Candida albicans, was achieved. Our research results enabled the access of all stereoisomers of 1 and the elucidation of the unknown absolute configuration of 1. Furthermore, one of the stereoisomers is a better amphotericin B potentiator than 1 and is an excellent lead compound for the development of a novel amphotericin B potentiator.


Subject(s)
Amphotericin B/pharmacology , Mannosides/chemistry , Mannosides/pharmacology , Pyrans/chemical synthesis , Pyrans/pharmacology , Candida albicans/drug effects , Chemistry Techniques, Synthetic , Drug Synergism , Mannosides/chemical synthesis , Microbial Sensitivity Tests , Pyrans/chemistry , Stereoisomerism
10.
Biochem Pharmacol ; 155: 61-70, 2018 09.
Article in English | MEDLINE | ID: mdl-29940173

ABSTRACT

The 'neurotrophic sesquiterpenes' refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other 'cage convulsant' compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.


Subject(s)
Convulsants/metabolism , Convulsants/pharmacology , Disease Progression , Neurodegenerative Diseases/metabolism , Sesquiterpenes/metabolism , Sesquiterpenes/pharmacology , Animals , Convulsants/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Locomotion/drug effects , Locomotion/physiology , Male , Mice , Nerve Growth Factors/chemistry , Nerve Growth Factors/metabolism , Nerve Growth Factors/pharmacology , Protein Binding/drug effects , Protein Binding/physiology , Protein Structure, Secondary , Psychomotor Agitation/metabolism , Sesquiterpenes/chemistry
11.
ChemMedChem ; 13(5): 411-421, 2018 03 06.
Article in English | MEDLINE | ID: mdl-29323466

ABSTRACT

Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO-1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O-acyltransferase 2 (SOAT2). To aid in the development of new cholesterol-lowering or anti-atherosclerotic agents, new A-ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure-activity relationship studies of pyripyropene A. Among the analogues, two A-ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A. These new analogues are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis.


Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Sesquiterpenes/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Aspergillus fumigatus/chemistry , CHO Cells , Cells, Cultured , Chlorocebus aethiops , Cricetulus , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Conformation , Pyridines/chemical synthesis , Pyridines/chemistry , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Sterol O-Acyltransferase/metabolism , Structure-Activity Relationship , Sterol O-Acyltransferase 2
12.
Org Lett ; 19(21): 5980-5983, 2017 11 03.
Article in English | MEDLINE | ID: mdl-29063763

ABSTRACT

Three new compounds, designated scopranones A-C, were isolated from the culture broth of a soil isolate, Streptomyces sp. BYK-11038, and shown to be inhibitors of bone morphogenetic protein (BMP) induced alkaline phosphatase activity in a BMP receptor mutant cell line. The structures were elucidated using NMR and other spectral data. The scopranones have an unusual structure with two atypical scooplike moieties linked at the tails to form part of a unique 3-furanone ring.

13.
J Am Chem Soc ; 139(28): 9637-9644, 2017 07 19.
Article in English | MEDLINE | ID: mdl-28644021

ABSTRACT

11-O-Debenzoyltashironin (1) is a member of the neurotrophic sesquiterpenes, trace plant metabolites that enhance neurite outgrowth in cultured neurons. We report its synthesis in six steps from a butenolide heterodimer via its likely biosynthetic precursor, 3,6-dideoxy-10-hydroxypseudoanisatin, here identified as the chain tautomer of 1. Access to the tashironin chemotype fills a gap in a comparison set of convulsive and neurotrophic sesquiterpenes, which we hypothesized to share a common target. Here we show that both classes mutually hyperexcite rat cortical neurons, consistent with antagonism of inhibitory channels and a mechanism of depolarization-induced neurite outgrowth.


Subject(s)
Bridged-Ring Compounds/chemical synthesis , GABA-A Receptor Antagonists/chemical synthesis , Animals , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , GABA-A Receptor Antagonists/chemistry , GABA-A Receptor Antagonists/pharmacology , HEK293 Cells , Humans , Molecular Structure , Neurons/drug effects , Neurons/metabolism , Rats , Receptors, GABA/metabolism , Stereoisomerism , Structure-Activity Relationship
14.
J Antibiot (Tokyo) ; 70(5): 647-654, 2017 May.
Article in English | MEDLINE | ID: mdl-28223689

ABSTRACT

Nafuredin-γ, obtained from natural nafuredin, has demonstrated a potent and selective inhibitory activity against nematode complex I. However, nafuredin-γ is unstable in air since its conjugated dienes are oxygen-labile. The instability in air was naturally solved by the synthesis of structure-simplified nafuredin-γ analogs without conjugated dienes. However, these modified analogs showed lower complex I inhibitory activities. Therefore, new air-stable structure-simplified nafuredin-γ analogs were designed and synthesized herein. Among all analogs synthesized, the one bearing a unique 1-azabicyclo[3.1.0]hexane scaffold showed the highest inhibitory activity (IC50=170 nM) while presenting high selectivity against nematode complex I.


Subject(s)
Antinematodal Agents/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Nematoda/drug effects , Pyrones/pharmacology , Animals , Antinematodal Agents/administration & dosage , Antinematodal Agents/chemistry , Drug Design , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Inhibitory Concentration 50 , Oxygen/chemistry , Pyrones/administration & dosage , Pyrones/chemistry , Structure-Activity Relationship
15.
Chem Pharm Bull (Tokyo) ; 64(9): 1370-7, 2016.
Article in English | MEDLINE | ID: mdl-27581641

ABSTRACT

Cyslabdan was isolated from the culture broth of Streptomyces sp. K04-0144 as a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus. We accomplished the synthesis of cyslabdan according to a previously reported structure. However, we subsequently found that this structure was incorrect; our analysis of natural cyslabdan showed that it possessed R stereochemistry at the C8 position, not S, as had previously been reported. Thus, we completed the protecting-group-free synthesis of the correct structure of cyslabdan, which is described herein.


Subject(s)
Acetylcysteine/analogs & derivatives , Diterpenes/chemistry , Diterpenes/chemical synthesis , Acetylcysteine/chemical synthesis , Acetylcysteine/chemistry , Molecular Conformation , Streptomyces/chemistry
16.
J Org Chem ; 81(17): 7373-83, 2016 09 02.
Article in English | MEDLINE | ID: mdl-27400027

ABSTRACT

The targets of antifungal antibiotics in clinical use are more limited than those of antibacterial antibiotics. Therefore, new antifungal antibiotics with different mechanisms of action are desired. In the course of our screening for antifungal antibiotics of microbial origins, new antifungal antibiotics, simplifungin (1) and valsafungins A (2) and B (3), were isolated from cultures of the fungal strains Simplicillium minatense FKI-4981 and Valsaceae sp. FKH-53, respectively. The structures of 1 to 3 including their absolute stereochemistries were elucidated using various spectral analyses including NMR and collision-induced dissociation (CID)-MS/MS as well as chemical approaches including modifications to the Mosher's method. They were structurally related to myriocin. They inhibited the growth of yeast-like and zygomycetous fungi with MICs ranging between 0.125 and 8.0 µg/mL. An examination of their mechanisms of action by the newly established assay using LC-MS revealed that 1 and 2 inhibited serine palmitoyltransferase activity, which is involved in sphingolipid biosynthesis, with IC50 values of 224 and 24 nM, respectively.


Subject(s)
Antifungal Agents/chemistry , Fatty Acids, Monounsaturated/chemistry , Antifungal Agents/pharmacology , Chromatography, Liquid , Fatty Acids, Monounsaturated/pharmacology , Fungi/drug effects , Fungi/growth & development , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Tandem Mass Spectrometry
17.
J Pharmacol Exp Ther ; 355(2): 299-307, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26338984

ABSTRACT

Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semisynthetic PPPA derivatives, potent, SOAT2-selective, and stable PRDs were selected. In vivo antiatherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe(-/-)) mice or low-density lipoprotein receptor knockout (Ldlr(-/-)) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe(-/-) mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9 ± 9.3%; further, the ratio of cholesteryl oleate to cholesteryl linoleate in low-density lipoprotein was lower by 55.6 ± 7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. The atherosclerotic lesion areas in the aortae of PRD125-treated mice were significantly lower at 62.2 ± 13.1%, respectively. Furthermore, both PRDs were also orally active in atherogenic Ldlr(-/-) mice. Among the PRDs tested, PRD125 was the most potent in both mouse models. These results suggest that SOAT2-selective inhibitors such as PRD125 have a high potential as poststatin agents for treatment and/or prevention in patients with atherosclerosis and hypercholesterolemia.


Subject(s)
Anticholesteremic Agents/chemistry , Atherosclerosis/drug therapy , Hypercholesterolemia/drug therapy , Pyridines/chemistry , Sesquiterpenes/chemistry , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Aorta/pathology , Apolipoproteins E/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , CHO Cells , Cholesterol/blood , Cholesterol Esters/blood , Cricetulus , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Lipid Droplets/metabolism , Lipoproteins/blood , Liver/metabolism , Male , Mice, Knockout , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, LDL/genetics , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Sterol O-Acyltransferase/metabolism , Structure-Activity Relationship , Sterol O-Acyltransferase 2
18.
Bioorg Med Chem ; 23(5): 932-43, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25659618

ABSTRACT

Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin-γ analogs. Although the complex I inhibitory activities of all the new nafuredin-γ analogs were lower than that of 2, all were in the high nM range (IC50: 300-820nM).


Subject(s)
Drug Design , Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrones/chemistry , Pyrones/pharmacology , Air , Drug Stability , Enzyme Inhibitors/chemical synthesis , Inhibitory Concentration 50 , Pyrones/chemical synthesis
19.
Bioorg Med Chem Lett ; 25(2): 313-6, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25488842

ABSTRACT

5-(4'-Methoxyphenyl)-oxazole (MPO), originally reported as a synthetic compound, was isolated from fungal culture broth as an inhibitor of hatch and growth of Caenorhabditis elegans. Nineteen MPO derivatives were chemically synthesized, but showed no effect on C. elegans hatch and growth. These findings strongly suggested that the whole structure of MPO is essential for anti-C. elegans activity.


Subject(s)
Antinematodal Agents/chemical synthesis , Antinematodal Agents/pharmacology , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/growth & development , Oxazoles/chemistry , Animals , Bacteria/drug effects , Cells, Cultured , Fungi/drug effects , Germ Cells/cytology , Germ Cells/drug effects , HeLa Cells , Humans , Molecular Structure , Structure-Activity Relationship
20.
J Antibiot (Tokyo) ; 68(1): 27-34, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25005817

ABSTRACT

Pyripyropene A (PPPA, 1) of fungal origin, a selective inhibitor of acyl-CoA:cholesterol acyltransferase 2 (ACAT2), proved orally active in atherogenic mouse models. The in vitro metabolites of 1 in liver microsomes and plasma of human, rabbit, rat and mouse were analyzed by ultra fast liquid chromatography and liquid chromatography/tandem mass spectrometry. In the liver microsomes from all species, successive hydrolysis occurred at the 1-O-acetyl residue, then at the 11-O-acetyl residue of 1, while the 7-O-acetyl residue was resistant to hydrolysis. Furthermore, dehydrogenation of the newly generated 11-alcoholic hydroxyl residue occurred in human and mouse-liver microsomes, while oxidation of the pyridine ring occurred in human and rabbit liver microsomes. On the other hand, hydrolysis of the 7-O-acetyl residue proceeded only in the mouse plasma. These data indicated that the in vitro metabolic profiles of 1 have subtle differences among animal species. All of the PPPA metabolites observed in liver microsomes and plasma markedly decreased ACAT2 inhibitory activity. These findings will help us to synthesize new PPPA derivatives more effective in in vivo study than 1.


Subject(s)
Chromatography, Liquid/methods , Microsomes, Liver/metabolism , Pyridines/metabolism , Sesquiterpenes/metabolism , Sterol O-Acyltransferase/antagonists & inhibitors , Tandem Mass Spectrometry/methods , Animals , Female , Humans , Hydrolysis , Male , Mice , Mice, Inbred C57BL , Rabbits , Rats , Rats, Sprague-Dawley , Rats, Wistar , Species Specificity , Sterol O-Acyltransferase 2
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