ABSTRACT
A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Drug Discovery/methods , Lung Neoplasms/enzymology , Oxamic Acid/analogs & derivatives , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Benzothiazoles/toxicity , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Female , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, SCID , Molecular Structure , Molecular Targeted Therapy , Oxamic Acid/pharmacokinetics , Oxamic Acid/pharmacology , Oxamic Acid/therapeutic use , Oxamic Acid/toxicity , Protein Binding , Sebaceous Glands/drug effects , Sebaceous Glands/enzymology , Sebaceous Glands/pathology , Xenograft Model Antitumor AssaysABSTRACT
A convergent total synthesis of the architecturally complex indole diterpenoid (-)-nodulisporic acid D has been achieved. Key synthetic transformations include vicinal difunctionalization of an advanced α,ß-unsaturated aldehyde to form the E,F-trans-fused 5,6-ring system of the eastern hemisphere and a cascade cross-coupling/indolization protocol leading to the CDE multisubstituted indole core.
Subject(s)
Indoles/chemical synthesisABSTRACT
A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Ethylenediamines/chemical synthesis , Ethylenediamines/pharmacology , Animals , Baculoviridae/genetics , Cell Line , Enzyme Inhibitors/pharmacokinetics , Ethylenediamines/pharmacokinetics , Humans , In Vitro Techniques , Indicators and Reagents , Insecta , Mice , Microsomes/drug effects , Microsomes/enzymology , Microsomes, Liver/metabolism , Myoblasts/drug effects , Myoblasts/enzymology , Oxidation-Reduction , Rats , Structure-Activity RelationshipABSTRACT
Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.
Subject(s)
Colonic Neoplasms/drug therapy , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Thiamine/analogs & derivatives , Thiamine/antagonists & inhibitors , Transketolase/antagonists & inhibitors , Animals , Colonic Neoplasms/enzymology , Crystallography, X-Ray , Glucosephosphate Dehydrogenase/metabolism , Humans , In Vitro Techniques , Ketoglutarate Dehydrogenase Complex/metabolism , Magnetic Resonance Spectroscopy , Mice , Mice, Nude , Molecular Structure , Oxythiamine/antagonists & inhibitors , Phosphorylation/drug effects , Spleen/drug effects , Spleen/enzymology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.
Subject(s)
Anti-HIV Agents/chemical synthesis , Drug Resistance, Viral , HIV Reverse Transcriptase/chemistry , Quinolones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Alkynes , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzoxazines , Binding Sites , Cell Line , Crystallography, X-Ray , Cyclopropanes , Drug Design , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , Humans , Models, Molecular , Molecular Structure , Mutation , Oxazines/chemistry , Quinolones/chemistry , Quinolones/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity. The USA BZDs were characterized by full agonism profiles. Copyright2000 Elsevier Science Ltd.
Subject(s)
Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , GABA-A Receptor Agonists , Animals , Benzodiazepines/pharmacokinetics , Chromatography, High Pressure Liquid , Humans , Postural Balance/drug effects , Rats , Receptors, GABA-A/metabolism , Structure-Activity RelationshipABSTRACT
The ultrashort-acting benzodiazepine (USA BZD) agonists reported previously have been structurally modified to improve aqueous solubility. Lactam-to-amidine modifications, replacement of the C5-haloaryl ring, and annulation of heterocycles are presented. These analogues retain BZD receptor potency and full agonism profiles.