Key Words: Amino acids I 1,2-Benzisoselenazol-3(2H)-ones I Cytokine inducers I Ebselen I Nitric oxide synthase inhibitors ned by reductive conversion of 1,2-benzisoselenazol-3(2H)-A convenient synthesis of the 2-carboxyalkyl-1,2-benzisose-ones 4 or directly by the reaction of bis[2-(chlorocarblenazol-3(2H)-ones 4a-k and their esters 41-p from 2-(chlo-onyl)phenyl] diselenide (3) with compounds having a prirose1eno)benzoyl chloride (2) and amino acids or their carb-mary amino group. It was found that some of compounds 4 oxy esters is reported. In similar way other 2-substituted 1,2-and 5 are modest cytokine (TNF, IFN) inducers in human pebenzisoselenazol-3(2H)-ones 4q-u were synthesized. The ripheral blood leucocyte cultures and block the constitutive related bis[2-(carbamoyl)phenyl] diselenides 5 were obtai-endothelial nitric oxide synthase (ce NOS).2-Phenyl-1,2-benzisoselenazol-3(2H)-one named ebselen was reported to be a non-toxic cocompound with antioxidant and antiinflammatory activity. More recently, other biological activities of this unique compound were also described"]. We found that ebselen blocks constitutive endothelial nitric oxide synthase and that it is a modest inducer of many different cytokines such as interferons (IFN, mainly IFN-y), tumor necrosis factor (TNF-a) as well as interleukin-2 and (IL-2, IL-6) gratunocyte-macrophate colony stimulating factor (GM-CSF)[2-61. In our previous work it was observed that some other 2-substituted 1,2-benzisoselenazol-3(2H)-ones, their 1 -oxides and organic diselenides, particularly bis[(2-~arbamoyl)phenyl] diselenides, are also able to induce cytokine synthesis, e.g. IFN and TNFr'I.Although a number of 1,2-benzisoselenazol-3(2H)-ones and bis[(2-carbamoyl)phenyl] diselenides were syntheonly a few of them contained strongly polar substituents such as the carboxyl g r o~p [~$~l .In this paper we report on the synthesis of 2-carboxyalkyl-and 2-carboxyaryl-l,2-benzisoselenazol-3(2H)-ones 4a-k, q, their alkyl esters 41-p, r, s and the related bis[(2-carbamoyl)phenyl] diselenides 5a-d, 1-0, q. Our interest was particularly directed to 2-carboxyalkyl-1,2-benzisoselenazol-3(2H)-ones 4a-k and their esters because these are members of the unique group of organoselenium compounds having an amino acid moiety built in the isoselenazole ring. For a comparison of the biological activity of 2-carboxyalkyl-1,2-benzisoselenazol-3(2H)-ones as cytokine inducers and NOS inhibitors with the activity of the compounds having no carboxyl or carboxy ester group, enantiomers of 2-( I-phenylethyl)-l,2-benzisoselenazol-3(2H)-ones (44 u) and related diselenides 5t, u were prepared.The reactions of 2-(chlorose1eno)benzoyl chloride (2) and bis[(2-~hlorocarbonyl)phenyl] diselenide (3) proceed as shown in Scheme 1. The dichloride 2 was prepared in high yield by reaction of bis(2-carboxyphenyl) diselenide (1) with thionyl chloride in the presence of DMF as a catalyst["l. Refluxing of the same reactants in benzene without a catalyst gave the diselenide 3 in 83% yield, substantially higher than t...
