ABSTRACT
We report on a new isomeric impurity of danazol. This impurity designated as isodanazol was detected by reversed-phase high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). Its structure was determined after separation by preparative HPLC. Mass spectrometry revealed the isomeric nature of the impurity while the UV spectrum indicated profound difference in the isoxazole moieties. The structure of the isomeric isoxazole ring in isodanazol was determined by NMR spectroscopy using COSY, HETCOR and NOE measurements. The difference between the UV spectra of danazol and isodanazol is explained on the basis of the difference between the aromaticities of their isoxazole rings supported by quantum chemical calculations. The quantitative determination of the impurity down to the 0.05% level can be performed by HPLC, gas chromatography and TLC densitometry.
Subject(s)
Danazol/analogs & derivatives , Danazol/analysis , Chromatography, Gas , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Danazol/isolation & purification , Densitometry , Drug Contamination , Isomerism , Magnetic Resonance Spectroscopy , Spectrophotometry, UltravioletABSTRACT
A series of potent inhibitors of NADPH- and Fe(2+)-dependent lipid peroxidation has been found among new pyrimido[1'6':1,2]pyrido[3,4-b]indole derivatives. According to preliminary structure-activity relationship analysis the saturated pyrimidine moiety was responsible for this effect. Some members of this family were effective in a bilateral carotid occlusion model in mice, and some derivatives showed protective effect in a mouse head injury model.
Subject(s)
Indoles/chemical synthesis , Lipid Peroxidation/drug effects , Animals , Brain/metabolism , Brain Ischemia/metabolism , Craniocerebral Trauma/metabolism , Female , In Vitro Techniques , Indoles/pharmacology , Iron/metabolism , Male , Mice , Mice, Inbred Strains , Microsomes/metabolism , NADP/metabolism , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The method of Lewis and coworkers for predicting the affinity of molecules for cytochrome P448 is studied. Parameters are modified to clarify their meaning and to simplify their calculation. Additional molecules are involved in the study. Geometric requirements for obtaining reliable parameters and the possibility of predicting carcinogenicity are discussed.
Subject(s)
Carcinogens/chemistry , Cytochromes/chemistry , Carcinogens/metabolism , Carcinogens/toxicity , Cytochrome P-450 CYP1A2 , Cytochromes/metabolism , Models, Theoretical , Structure-Activity RelationshipABSTRACT
A model of the active site of cytochrome P-450 nifedipine oxidase is built on the basis of sequence homology with cytochrome P-450CAM. Substrates are docked into the binding pocket, and molecular mechanical energy minimization is performed to analyze the forces between the substrates and the enzyme.
