Synthesis and Properties of 2‐Carboxyalkyl‐1,2‐benzisoselenazol‐3(2H)‐ones and Related Organoselenium Compounds as Nitric Oxide Synthase Inhibitors and Cytokine Inducers

Abstract

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...

Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties

“…Both benzoyl chlorides 3 and 5 were obtained in a three-step synthesis starting from anthranilic acid (1), which was diazotized and reacted with dilithium diselenide in aprotic medium (THF) to give after acidification 2,2'-diselenobisbenzoic acid 2 with 78 % yield. [28][29][30] Efficient cooling is important to reduce by-product formation such as salicylic acid. Dilithium diselenide was generated in situ from elemental lithium and selenium in the presence of 4,4'-di(tbutyl)biphenyl, as a catalyst.…”

“…20 The acid 2 was easily converted into 2-(chloroseleno)benzoyl chloride (3) (85%) with thionyl chloride, used in excess, in the presence of catalytic amounts of N,N'-dimethylformamide. 29 When thionyl chloride was used in excess (2.5 equivalents), chloride 5 (64%) was produced. 29 The reaction of benzoyl chlorides 3 and 5 with anilines substituted at ortho, meta or para positions of the phenyl ring by electron-donating methyl and/or strong electron-donating methoxy groups, (in some cases with a chlorine substituent) provides a straightforward way to obtain new mono and disubstituted 2-phenylbenzisoselanzol-3(2H)-ones 4 and bis(2-carbamoylaryl) diselenides 6, respectively.…”

“…29 When thionyl chloride was used in excess (2.5 equivalents), chloride 5 (64%) was produced. 29 The reaction of benzoyl chlorides 3 and 5 with anilines substituted at ortho, meta or para positions of the phenyl ring by electron-donating methyl and/or strong electron-donating methoxy groups, (in some cases with a chlorine substituent) provides a straightforward way to obtain new mono and disubstituted 2-phenylbenzisoselanzol-3(2H)-ones 4 and bis(2-carbamoylaryl) diselenides 6, respectively. All products were prepared with good to excellent yields (Scheme 1).…”

“…29 Crude oily product was recrystallized from nhexane and dried under vacuum (200 mmHg) to give 2-(chloroseleno)benzoyl chloride (3) as yellow needles, mp 65-67 °C (lit. 29 …”

Diaryl diselenides and benzisoselenazol-3(2H)-ones as oxygen-transfer agents

“…A more general method for the synthesis of ebselen and other 2-substituted benzisoselenazol-3(2H)-ones (90) as well as for synthesis of 2-carbamoylphenyl diselenides (83), presented in Scheme 21, was elaborated in our laboratory as a modification of the old procedure reported by Lesser and Weiss. 48,50,51 The first two steps of the synthesis involve diazotization of anthranilic acid (86) and repleacement of the diazonium group by the diselenide group by treatment of a diazonium salt with disodium diselenide, generated in situ from elemental selenium and hydrazine hydrate in the presence of sodium hydroxide. The formed 2,2'-diselenobisbenzoic acid (87), treated with an excess of thionyl chloride in the presence of catalytical amounts of DMF, gives 2-(chloroseleno)benzoyl chloride (89), or when thionyl chloride is used a stoichiometric amount 2,2'-diselenobis benzoyl chloride (88) is produced.…”