Synthesis and characterization of thiol containing furoxan derivatives as coligands for the preparation of potential bioreductive radiopharmaceuticals.

The synthesis and characterization of thiol-containing 1,2,5-oxadiazole N-oxide (TONO) derivatives and their use as monodentate coligands for the preparation of (99m)Tc complexes is presented. 3-Mercaptomethyl-4-phenyl-1,2,5-oxadiazol N(2)-oxide and 3-(4-mercaptophenylmethylidenhydrazinocarbonyloxymethyl)-4-phenyl-1,2,5-oxadiazol N(2)-oxide were successfully synthesized and combined with the tridentate ligand N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) to prepare "3+1 mixed ligand" technetium complexes. The( 99m)Tc complexes were obtained in high yield and radiochemical purity using low concentration of ligand and coligand. An alternative procedure using a xantate and a disulphide precursor of 3-mercaptomethyl-4-phenyl-1,2,5-oxadiazol N(2)-oxide yielded the same complex. Biological evaluation of the potentiality of the( 99m)Tc complexes as bioreductive radiopharmaceuticals was performed in normal CD1 mice and in mice bearing induced sarcoma. Tumour uptake was moderate but tumour/soft tissue ratio was favourable. Although these results are encouraging, further development is still necessary in order to achieve higher tumour uptake and lower gastrointestinal activity.

Relationship between physicochemical properties and herbicidal activity of 1,2,5-oxadiazole N-oxide derivatives.

The relationship between the herbicidal activity of a number of novel 1,2,5-oxadiazole N-oxides and some physicochemical properties potentially related with this bioactivity, such as polarity, molecular volume, proton acceptor ability, lipophilicity, and reduction potential were studied. The semiempirical molecular orbital method AM1 was used to calculate theoretical descriptors such as dipolar moment, molecular volume, Mulliken's charge and the octanol/water partition coefficients (log P(o/w)). The values of the reduction potentials (E(r)) were obtained by cyclic voltammetry. In addition, the retention factors (log (k'w)) on a reversed-phase high-performance liquid chromatography(RP-HPLC) column in pure aqueous mobile phases were measured for several N-oxide derivatives. The log (k'w) values show good correlation with the calculated values of log P(o/w), showing that the chromatographic parameter can be used as lipophilicity descriptor for these compounds. The multiple regression analysis between the descriptors for the N-oxide derivatives and the herbicide activity indicate that the variance in the biological activity can be explained by changes in the lipophilicity and in the reduction potential.

1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part III.

New 5-(2-arylethenyl)-1, 2, 4-triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The desired products were obtained when the 5-methyl heterocycle reacted with the corresponding iminium electrophiles. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than Tirapazamine, 3-aminobenzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 11, 6-methyl-5-[2-(5-nitrofuryl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective. Some derivatives were studied as DNA-binding agents in oxic conditions showing poor affinity for this biomolecule. This result showed that the cytotoxic activity in oxia is DNA damage not dependent. Electrochemical and ESR spectroscopy studies were performed in order to determine the ability of compounds to produce radicals and the relation of these in the mechanism of cytotoxicity.

Electrochemical and microsomal production of free radicals from 1,2,5-oxadiazole N-oxide as potential antiprotozoal drugs.

The electron spin resonance (ESR) spectra of free radicals obtained by electrolytic or microsomal reduction of several potential antiprotozoal 1,2,5-oxadiazoles were characterized and analyzed. Ab initio molecular orbital calculations were performed to obtain the optimized geometries and the theoretical hyperfine constant was carried out using ZINDO semiempirical methodology. Density functional theory was used to rationalize the reduction potentials of these compounds.