ABSTRACT
Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.
Subject(s)
Antineoplastic Agents/chemical synthesis , CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hydrazones/chemical synthesis , Indoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Cyclin-Dependent Kinase 2 , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , G1 Phase/drug effects , Humans , Hydrazones/chemistry , Hydrazones/pharmacology , Indoles/chemistry , Indoles/pharmacology , Isatin/analogs & derivatives , Isatin/chemical synthesis , Isatin/chemistry , Models, Molecular , Protein Binding , S Phase/drug effects , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Tumor Cells, CulturedABSTRACT
Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.
Subject(s)
Alopecia/chemically induced , Alopecia/prevention & control , Antineoplastic Agents/toxicity , CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hair Follicle/drug effects , Indoles/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Animals, Newborn , Antineoplastic Combined Chemotherapy Protocols/toxicity , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinases/metabolism , Cyclophosphamide/toxicity , Cytoprotection/drug effects , DNA/biosynthesis , Doxorubicin/toxicity , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Epithelium/drug effects , Etoposide/toxicity , Hair Follicle/cytology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Mice , Mice, SCID , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Rats , Retinoblastoma Protein/metabolism , Scalp/transplantation , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Transplantation, HeterologousABSTRACT
A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway.
Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Enzyme Inhibitors/chemistry , MAP Kinase Signaling System , Structure-Activity RelationshipABSTRACT
A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with K(i) values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue. The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Quinazolines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Animals , Anti-Infective Agents/toxicity , Antineoplastic Agents/toxicity , Brain Neoplasms/drug therapy , Candidiasis/drug therapy , Cell Division/drug effects , Cell Line , Crystallography, X-Ray , Drug Design , Drug Resistance, Multiple , Enzyme Inhibitors/pharmacology , Folic Acid Antagonists/chemistry , Humans , Lung Neoplasms/drug therapy , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Nude , Mice, SCID , Models, Molecular , Molecular Conformation , Molecular Structure , Molecular Weight , Pneumonia, Pneumocystis/drug therapy , Protein Structure, Secondary , Quinazolines/toxicity , Structure-Activity Relationship , Toxoplasma/drug effects , Tumor Cells, CulturedABSTRACT
A technique has been described for making accurate fitting acrylic resin provisional restorations with attention to marginal adaptation and ease of fabrication.
