ABSTRACT
BACKGROUND: A number of compounds were examined for their inhibitory effects on bovine viral diarrhoea virus (BVDV), a surrogate model of hepatitis C virus, in cell cultures. Among them, some diphenylmethane derivatives were found to be selective inhibitors of BVDV. METHODS: Determination of compounds for their anti-BVDV activity was based on the inhibition of virus-induced cytopathic effect in Madin-Darby bovine kidney cells and reduction of infectious virus particles in culture supernatants. To gain insight into the mechanism of action, the inhibition of viral entry and RNA synthesis in the host cells was also determined by real-time reverse transcription-PCR. RESULTS: Among the test compounds, four diphenylmethane derivatives significantly inhibited BVDV replication with a 50% effective concentration ranging between 6.3 and 10.8 muM. They were not cytotoxic at concentrations up to 100 muM. The representative compound, SH-595A, reduced the virus titre of culture supernatants in a dose-dependent manner. In addition, the compound appeared to somewhat affect viral entry to the host cells. Although SH-595A was inhibitory to viral RNA synthesis, the inhibition was achieved only at high concentrations and was not comparable to its antiviral activity. CONCLUSIONS: The novel diphenylmethane derivatives are effective against BVDV replication and might have a unique mechanism of action.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Diarrhea Viruses, Bovine Viral/drug effects , Antigens, Viral/metabolism , Cell Line , Diarrhea Viruses, Bovine Viral/metabolism , Diarrhea Viruses, Bovine Viral/physiology , Dose-Response Relationship, Drug , RNA, Viral/biosynthesis , Virus Internalization/drug effects , Virus Replication/drug effectsABSTRACT
Based on our hypothesis that the 3,3-diphenylpentane (DPP) skeleton is useful as a multi-template for creation of various biologically active compounds and acts as a steroid skeleton substitute, we designed and synthesized novel HMG-CoA reductase inhibitors with a DPP skeleton. Among them, sodium (E,3R,5S)-7-(2-(4-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl)-3,5-dihydroxy-hept-6-enoate showed potent HMG-CoA reductase-inhibitory activity comparable with that of clinically useful mevastatin.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pentanes/chemical synthesis , Androgens/chemistry , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Lovastatin/analogs & derivatives , Lovastatin/chemical synthesis , Lovastatin/pharmacology , Models, Chemical , Molecular Structure , Pentanes/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
As an example of a multi-template approach, we focused on the 3,3-diphenylpentane (DPP) skeleton, which has been demonstrated to act as a steroid skeleton substitute. Various ligands for nuclear receptors (NRs), including vitamin D receptor (VDR), androgen receptor (AR) and farnesoid X receptor (FXR), and inhibitors of steroid metabolism-related enzymes, including 5alpha-reductase and HMG-CoA reductase (HMGR), have been efficiently created by introducing various substituents onto the DPP skeleton.
Subject(s)
Enzymes/metabolism , Pentanes/chemistry , Pentanes/metabolism , Receptors, Steroid/metabolism , Steroids/chemistry , Steroids/metabolism , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Ligands , Pentanes/pharmacologyABSTRACT
Based on antiviral screening of our diphenylmethane derivatives prepared as steroid substitutes, we identified a 1,1-diphenylcyclobutane analog (9) and two diethyldiphenylsilane analogs (12 and 13) as superior lead compounds with potent anti-bovine viral diarrhea virus (BVDV) activity, having 50% effective concentration (EC(50): based on reduction of BVDV replication-induced cell destruction) and 50% cytotoxic concentration (CC(50): based on reduction of viable cell number) values of 6.2-8.4 microM and >100 microM, respectively, in Madin-Darby bovine kidney (MDBK) cells infected with BVDV.
Subject(s)
Antiviral Agents/chemistry , Benzhydryl Compounds/chemistry , Diarrhea Viruses, Bovine Viral/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacology , Bovine Virus Diarrhea-Mucosal Disease/drug therapy , Cattle , Cell Line , Cell Survival/drug effects , Drug Evaluation, Preclinical , Steroids/chemistry , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
We designed and synthesized novel type 1 5alpha-reductase inhibitors by using 3,3-diphenylpentane skeleton as a substitute for the usual steroid skeleton. 4-(3-(4-(N-Methylacetamido)phenyl)pentan-3-yl)phenyl dibenzylcarbamate (11k) is a competitive 5alpha-reductase inhibitor with the IC(50) value of 0.84 microM.
Subject(s)
5-alpha Reductase Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pentanes/chemical synthesis , Pentanes/pharmacology , Cell Line, Tumor , Dose-Response Relationship, Drug , Finasteride/pharmacology , Humans , Indicators and Reagents , Structure-Activity RelationshipABSTRACT
Convenient synthesis of a variety of photoaffinity probes was accomplished by utilizing our Ns strategy and novel resin. The synthetic probes were evaluated via the labeling ability with the preseniline 1 C-terminal fragments, which was identified as a therapeutic target for Alzheimer's disease.
Subject(s)
Photoaffinity Labels/chemistry , Photoaffinity Labels/chemical synthesis , Presenilin-1/chemistry , Molecular Structure , Photoaffinity Labels/analysisABSTRACT
Ligands possessing dual vitamin D(3) (VD(3))-agonistic and androgen-antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane (DPP) skeleton. Among the compounds, (R,S)-DPP-1023 [(R,S)-7b] and (S,S)-DPP-0123 [(S,S)-7c] showed the most potent vitamin D(3)-agonistic activity [with potency comparable to that of 1alpha,25-dihydroxyvitamin D(3) (1,25-VD(3))] and nuclear androgen receptor (AR)-binding activity (with higher affinity than that of hydroxyflutamide), respectively. Metabolic activation (reduction of the carbonyl group) of pivaloyl analogs [DPP-1113 (3a), DPP-1013 (3b), DPP-0113 (3c), and DPP-0013 (3d)] in HL-60 cells was found to be necessary for binding to nuclear vitamin D(3) receptor (VDR).
Subject(s)
Benzhydryl Compounds/pharmacology , Cell Proliferation/drug effects , Receptors, Androgen/metabolism , Vitamin D/pharmacology , Androgen Receptor Antagonists , Benzhydryl Compounds/chemical synthesis , Binding Sites , Dose-Response Relationship, Drug , HL-60 Cells , Humans , Ligands , Molecular Structure , Vitamin D/agonists , Vitamin D/analogs & derivatives , Vitamin D/chemical synthesis , Vitamin D-Binding Protein/metabolismABSTRACT
Novel, potent farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor alpha (PPARalpha) agonists were obtained by using a diphenylmethane skeleton as a substitute for a steroid skeleton.
Subject(s)
Benzhydryl Compounds/chemistry , Benzhydryl Compounds/metabolism , DNA-Binding Proteins/agonists , DNA-Binding Proteins/metabolism , PPAR alpha/agonists , PPAR alpha/metabolism , Transcription Factors/agonists , Transcription Factors/metabolism , Benzhydryl Compounds/chemical synthesis , DNA-Binding Proteins/genetics , Humans , Ligands , Molecular Structure , Receptors, Cytoplasmic and Nuclear , Transcription Factors/genetics , Transcription, Genetic/geneticsABSTRACT
Ligands possessing dual vitamin D3-agonistic (estimated as HL-60 monocytic cell differentiation induction) and androgen-antagonistic (estimated as testosterone-induced SC-3 cell growth inhibition) activities with various activity spectra were prepared based on a substituted bis-phenylmethane skeleton. Some of them were revealed to be potent androgen antagonists with a nonsecosteroidal vitamin D3 skeleton.
