ABSTRACT
This report details a method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) that allows one to determine the concentration of an atypical anticancer drug, enzalutamide, in rat plasma. Specifically, this method involves the addition of an acetonitrile and bicalutamide (internal standard) solution to plasma samples. Following centrifugation of this mixture, an aliquot of the supernatant was directly injected into the LC-MS/MS system. Separation was achieved using a column packed with octadecylsilica (5 µm, 2.1 × 50 mm) with 10 mM ammonium acetate in acetonitrile as the mobile phase; detection was accomplished using MS/MS by multiple-reaction monitoring via an electrospray ionization source. This method demonstrated a linear standard curve (r = 0.997) over a concentration range of 0.001-1 µg/mL, as well as an intra- and inter-assay precision of 2.7 and 5.1%, respectively, and an accuracy range from 100.8 to 105.6%. The lower limit of quantification was 1.0 ng/mL in 50 µL of rat plasma sample. We also demonstrated that this analytical method could be successfully applied to the pharmacokinetic study of enzalutamide in rats.
Subject(s)
Antineoplastic Agents/blood , Chromatography, High Pressure Liquid/methods , Phenylthiohydantoin/analogs & derivatives , Tandem Mass Spectrometry/methods , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Benzamides , Linear Models , Male , Nitriles , Phenylthiohydantoin/blood , Phenylthiohydantoin/chemistry , Phenylthiohydantoin/pharmacokinetics , Prostatic Neoplasms , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
In this study, we synthesized the BF-3 binding small molecules, a series of pyridazinone-based compounds, as a novel class of non-LBP antiandrogens for treating prostate cancer by inhibiting androgen receptor. The new class compound was discovered to inhibitor the viability of AR-dependent human prostate LNCap cells and AR activity combining with the computational method. It showed a good physicochemical and PK property.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Models, Molecular , Molecular Structure , Prostatic Neoplasms/pathology , Pyridazines/administration & dosage , Pyridazines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Poly(ADP-ribose)polymerase-1 (PARP-1) enzyme is involved in the repair of DNA damages made by certain anticancer agents. It is suggested that PARP-1 inhibitors potentiate the cytotoxic effects and circumvent the resistance of DNA-modifying anticancer agents such as cisplatin. In this study, we conducted virtual screening of Korea Chemical Bank database targeting PARP-1 and identified several potent PARP-1 inhibitors with submicromolar IC50 values (77-79 nM). We then examined the chemosensitization of cisplatin by pre-treatment of PARP-1 inhibitors in cisplatin-resistant human gastric cancer cells. Our results show that PARP-1 inhibitors suppress the formation of poly(ADP-ribose) and enhance the cytotoxicity of cisplatin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemistry , Poly(ADP-ribose) Polymerase Inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Binding Sites , Catalytic Domain , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/therapeutic use , Databases, Factual , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Humans , Molecular Docking Simulation , Poly(ADP-ribose) Polymerases/metabolism , Stomach Neoplasms/drug therapy , Stomach Neoplasms/enzymologyABSTRACT
Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of structure-activity relationship studies led to the identification of compound 4c as a potent MCH-R1 antagonist (IC(50)=1 nM). This compound also has good metabolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found to be potent inhibitor of the hERG potassium channel.
Subject(s)
Acetanilides/chemical synthesis , Benzimidazoles/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Acetanilides/chemistry , Acetanilides/pharmacokinetics , Administration, Oral , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Brain/metabolism , Humans , Rats , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
(+)-Monomorine has been synthesized under mild hydrogenation conditions initiating deprotection followed by intramolecular, sequential reductive amination reactions. The precursors could be prepared concisely using B-alkyl Suzuki cross coupling of a chiral homoallylamine and a vinyl iodide or an iodofuran derivative.
Subject(s)
Alkaloids/chemical synthesis , Combinatorial Chemistry Techniques , Indolizines/chemical synthesis , Catalysis , Hydrogenation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , StereoisomerismABSTRACT
A series of 4-(N-imidazol-2-ylmethyl)aminobenzopyran analogues, originally designed as K(ATP) openers for ischemic diseases, showed antiangiogenic properties through the inhibition of HUVEC tube formation. Especially one of p-Cl substituted analogues (4c) completely inhibited HUVEC tube formation at 10 microM. The compound 4c significantly inhibited tumor growth by 52% on A549 (human non small cell lung carcinoma) in nude mice xenografts without any significant side effects.