Synthesis and study of new paramagnetic and diamagnetic verapamil derivatives.

New derivatives of verapamil (1) modified with nitroxides and their precursors were synthesized and screened for reactive oxygen species (ROS)-scavenging activities. The basic structure was modified by changing the nitrile group to an amide or the methyl substituent on tertiary nitrogen with nitroxides and their reduced forms (hydroxylamine and secondary amines). Among the new verapamil derivatives compound 16B [Mohan, I.

Studies of structure-activity relationship of nitroxide free radicals and their precursors as modifiers against oxidative damage.

The protective effects of stable nitroxides, as well as their hydroxylamine and amine precursors, have been tested in Chinese hamster V79 cells subjected to H2O2 exposure at fixed concentration or exposure to ionizing radiation. Cytotoxicity was evaluated by monitoring the viability of the cells assessed by the clonogenic assay. The compounds tested at fixed concentration varied in terms of ring size, oxidation state, and ring substituents.

Direct evidence for in vivo nitroxide free radical production from a new antiarrhythmic drug by EPR spectroscopy.

The new Class I anti-arrhythmic agent 2,2,5,5-tetramethyl-3-pyrroline-1-carboxamide derivative, is currently being evaluated in clinical trials in patients with a high risk for cardiac arrhythmias. In this study we show that this antiarrhythmic drug can be chemically converted to the nitroxide free radical analog. Further, using an in vivo Electron Paramagnetic Resonance (EPR) spectroscopy model by detecting free radicals in the distal portion of the tail of an anesthetized mouse, we demonstrate that the drug is oxidized to the corresponding nitroxide.

pKa values and partition coefficients of nitroxide spin probes for membrane bioenergetics measurements.

Knowledge of pKa's is necessary to calculate intracellular/intravesicular pH values from nitroxide accumulation in cells or vesicles as detected with electron spin resonance (ESR) spectroscopy. pKa values were confirmed in lipid vesicles of known internal pH. To help select probes that do not accumulate in lipid membranes, octanol/buffer partition coefficients of uncharged nitroxides were determined.

New antiarrhythmic agents. 2,2,5,5-Tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5-tetramethylpyrrolidine-3-carboxamindes.

N-(omega-Aminoalkyl)-2,2,5,5-tetramethyl-3-pyrroline- or -pyrrolidine-3-carboxamides were acylated on the primary amino group of the side chain by means of reactive acid derivatives (acid chlorides, activated esters, phthalic anhydrides, phthalimide, 2-alkyl-4H-3,1-benzoxazin-4-ones) or they were alkylated by forming the Schiff bases and subsequent sodium borohydride reduction. Other tetramethyl-3-pyrrolinecarboxamide compounds were synthesized by acylating the aminoalkyl compounds with 2,2,6,6-tetramethyl-3,5-dibromo-4-piperidinone in a reaction involving Favorskii rearrangement. Saturation of the double bond of some pyrroline derivatives furnished the pyrrolidinecarboxamides.