The Furoxan System: Design of Selective Nitric Oxide (NO) Donor Inhibitors of COX-2 Endowed with Anti-Aggregatory and Vasodilating Activities

Abstract

Several NO donor 3,4-diphenylfuroxan (= 3,4-diphenyl-1,2,5-oxadiazole 2-oxide) derivatives were synthesized and tested for their COX-inhibiting activities. The products were found to be selective COX-2 inhibitors, similar to the structurally related furazans (3,4-diphenyl-1,2,5-oxadiazole), devoid of the NO release property. This behavior was confirmed by a molecular-docking study. The NO-dependent platelet anti-aggregatory and vasodilating activities of the new furoxans 5-7 were studied in vitro. These properties can be modulated by inserting an appropriate spacer between the 4-phenyl group and the furoxan ring, giving rise to new, selective COX-2 furoxan derivatives endowed with anti-aggregatory and vasodilating activities, and with potentially reduced cardiotoxicities.

Nitrooxymethyl‐Substituted Analogues of Celecoxib: Synthesis and Pharmacological Characterization

“…NO displays a variety of effects in the cardiovascular system, including vasodilation, inhibition of platelet aggregation, modulation of platelet and leukocytes adherence to vessels, and inhibition of smooth muscle cell proliferation [7]. Examples of this type of approach have already been reported [8] [9] including by our group [10] [11]. As a development of our work in this field, we now describe the synthesis and structural characterization of a new series of NO-donor COX-2 inhibitors obtained by introducing NO-donor nitrooxy functions into the well-known selective COX-2 inhibitor celecoxib (1) [12] that has recently been placed under surveillance by FDA, following its suspected cardiotoxicity.…”

Nitric oxide affects immune cells bioenergetics

“…The AT38 used herein is a NSAID consisting of a salicylic acid (SA)-like moiety linked to a furoxan moiety (details for AT38 structure, formulation and release mechanisms will be fully described in another submitted manuscript). These furoxan based-NO donors are now emerging for the selective inhibition of cyclooxygenase, including their use for the treatment of certain cancer types and neurological disorders (Del Grosso et al 2005). We also compared the effects of NO donors to nitrite and nitrate donors (NaNO 2 and NaNO 3 , respectively) on Jurkat cell bioenergetics and showed a time-and concentration-dependent immunosuppressive potential of nitrate.…”

Synthesis and Synthetic Application of Chloro- and Bromofuroxans

“…C− C bond formation on the furoxan ring has been underdeveloped. Before we began our investigation of C−C bond formation on the furoxan ring, only one report by Del Gasco et al 15 was available in the literature, in which two selected substrates reacted with an aryl Grignard reagent. Recently, our group developed the alkynylation of 4-nitro-and 4sulfonylfuroxans, which represented the first general reaction for C−C bond formation on furoxan rings.…”