Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 50(8): 1850-64, 2007 Apr 19.
Article in English | MEDLINE | ID: mdl-17381079

ABSTRACT

The 3C-like protease (3CLpro), which controls the severe acute respiratory syndrome (SARS) coronavirus replication, has been identified as a potential target for drug design in the treatment of SARS. A series of tetrapeptide phthalhydrazide ketones, pyridinyl esters, and their analogs have been designed, synthesized, and evaluated as potential SARS 3CLpro inhibitors. Some pyridinyl esters are identified as very potent inhibitors, with IC50 values in the nanomolar range (50-65 nM). Electrospray mass spectrometry indicates a mechanism involving acylation of the active site cysteine thiol for this class of inhibitors.


Subject(s)
Antiviral Agents/chemical synthesis , Cysteine Endopeptidases/chemistry , Ketones/chemical synthesis , Oligopeptides/chemical synthesis , Phthalazines/chemical synthesis , Pyridines/chemical synthesis , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Antiviral Agents/chemistry , Binding Sites , Biomimetics , Combinatorial Chemistry Techniques , Coronavirus 3C Proteases , Esters , Ketones/chemistry , Models, Molecular , Oligopeptides/chemistry , Phthalazines/chemistry , Pyridines/chemistry , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Structure-Activity Relationship
2.
J Med Chem ; 47(25): 6113-6, 2004 Dec 02.
Article in English | MEDLINE | ID: mdl-15566280

ABSTRACT

The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the alpha-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC(50) values ranging from 0.60 to 70 microM.


Subject(s)
Antiviral Agents/chemical synthesis , Glutamine/analogs & derivatives , Glutamine/chemical synthesis , Ketones/chemical synthesis , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Coronavirus 3C Proteases , Cysteine Endopeptidases , Endopeptidases/chemistry , Glutamine/chemistry , Ketones/chemistry , Models, Molecular , Structure-Activity Relationship , Viral Proteins/chemistry
3.
Bioorg Med Chem ; 12(7): 1667-87, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-15028260

ABSTRACT

A series of quinolinequinones bearing various substituents has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (hNQO1) was studied. A range of quinolinequinones were selected for study, and were specifically designed to probe the effects of aryl substituents at C-2. A range of 28 quinolinequinones 2-29 was prepared using three general strategies: the palladium(0) catalyzed coupling of 2-chloroquinolines, the classical Friedländer synthesis and the double-Vilsmeier reaction of acetanilides. One example of an isoquinolinequinone 30 was also prepared, and the reduction potentials of the quinones were measured by cyclic voltammetry. For simple substituents R(2) at the quinoline 2-position, the rates of quinone metabolism by hNQO1 decrease for R(2)=Cl>H approximately Me>Ph. For aromatic substituents, the rate of reduction decreases dramatically for R(2)=Ph>1-naphthyl>2-naphthyl>4-biphenyl. Compounds containing a pyridine substituent are the best substrates, and the rates decrease as R(2)=4-pyridyl>3-pyridyl>2-pyridyl>4-methyl-2-pyridyl>5-methyl-2-pyridyl. The toxicity toward human colon carcinoma cells with either no detectable activity (H596 or BE-WT) or high NQO1 activity (H460 or BE-NQ) was also studied in representative quinones. Quinones that are good substrates for hNQO1 are more toxic to the NQO1 containing or expressing cell lines (H460 and BE-NQ) than the NQO1 deficient cell lines (H596 and BE-WT).


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , NAD(P)H Dehydrogenase (Quinone)/chemistry , NAD(P)H Dehydrogenase (Quinone)/metabolism , Quinones/chemistry , Quinones/metabolism , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Electrochemistry , Humans , Molecular Structure , NAD(P)H Dehydrogenase (Quinone)/drug effects , Oxidation-Reduction/drug effects , Quinones/chemical synthesis , Recombinant Proteins/metabolism , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...