Konstantin Chegaev

Phenylsulfonylfuroxans as Modulators of Multidrug-Resistance-Associated Protein-1 and P-Glycoprotein

A series of furoxan derivatives were studied for their ability to interact with P-gp and MRP1 transporters in MDCK cells overexpressing these proteins. 3-Phenylsulfonyl substituted furoxans emerged as the most interesting compounds. All of them were capable of inhibiting P-gp, and a few also were capable of inhibiting MRP1. Substituents at the 4-position of 3-phenylsulfonylfuroxan scaffold were able to modulate the selectivity and the intensity of inhibition. In some cases, they reverted MRP1 inhibitor activity, namely, they were capable of potentiating MRP1 dependent efflux. When compounds 16 and 17 were coadministered with doxorubicin, they restored a high degree of the activity of the antibiotic. Preliminary immunoblotting studies carried out on these two compounds indicate that they are capable of nitrating P-gp, which in this form is likely unable to efflux the antibiotic.

Nitric oxide donor doxorubicins accumulate into Doxorubicin-resistant human colon cancer cells inducing cytotoxicity.

Products 4 and 5, obtained by conjugation of doxorubicin with nitric oxide (NO) donor nitrooxy and phenylsulfonyl furoxan moieties, respectively, accumulate in doxorubicin-resistant human colon cancer cells (HT29-dx), inducing high cytotoxicity. This behavior parallels the ability of the compounds to generate NO, detected as nitrite, in these cells. Preliminary immunoblotting studies suggest that the mechanism that underlies the cytotoxic effect could involve inhibition of cellular drug efflux due to nitration of tyrosine residues of the MRP3 protein pump.

Mitochondrial-Targeting Nitrooxy-doxorubicin: A New Approach To Overcome Drug Resistance

In previous studies, we showed that nitric oxide (NO) donors and synthetic doxorubicins (DOXs) modified with moieties containing NO-releasing groups--such as nitrooxy-DOX (NitDOX) or 3-phenylsulfonylfuroxan-DOX (FurDOX)--overcome drug resistance by decreasing the activity of ATP-binding cassette (ABC) transporters that can extrude the drug. Here, we have investigated the biochemical mechanisms by which NitDOX and FurDOX exert antitumor effects. Both NitDOX and FurDOX were more cytotoxic than DOX against drug-resistant cells. Interestingly, NitDOX exhibited a faster uptake and an extranuclear distribution. NitDOX was preferentially localized in the mitochondria, where it nitrated and inhibited the mitochondria-associated ABC transporters, decreased the flux through the tricarboxylic acid cycle, slowed down the activity of complex I, lowered the synthesis of ATP, induced oxidative and nitrosative stress, and elicited the release of cytochrome c and the activation of caspase-9 and -3 in DOX-resistant cells. We suggest that NitDOX may represent the prototype of a new class of multifunctional anthracyclines, which have cellular targets different from conventional anthracyclines and greater efficacy against drug-resistant tumors.

Edaravone derivatives containing NO-donor functions.

A new series of polyvalent drugs obtained by joining edaravone with NO-donor moieties is described. All compounds display high antioxidant power together with NO-dependent vasodilator properties. The analysis of a number of molecular descriptors shows that the antioxidant activity, which is tightly linked to the presence of the edaravone substructure, is principally modulated by lipophilicity. These products are potentially useful in the treatment of cardiovascular disorders in which EDRF deficiency and ROS excess are involved.

New Nitric Oxide or Hydrogen Sulfide Releasing Aspirins

A new series of (((R-oxy)carbonyl)oxy)methyl esters of aspirin (ASA), bearing nitric oxide (NO) or hydrogen sulfide (H(2)S) releasing groups, was synthesized, and the compounds were evaluated as new ASA co-drugs. All the products were quite stable in buffered solution at pH 1 and 7.4. Conversely, they were all rapidly metabolized, producing ASA and the NO/H(2)S releasing moiety used for their preparation. Consequent on ASA release, the compounds were capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma (PRP). The simple NO/H(2)S donor substructures were able to relax contracted rat aorta strips, with a NO- and H(2)S-dependent mechanism, respectively, but they either did not trigger antiaggregatory activity or displayed antiplatelet potency markedly below that of the related co-drug. The new products might provide a safer and improved alternative to the use of ASA principally in its anti-inflammatory and antithrombotic applications.

Nitrooxyacyloxy)methyl Esters of Aspirin as Novel Nitric Oxide Releasing Aspirins

A series of (nitrooxyacyloxy)methyl esters of aspirin were synthesized and evaluated as new NO-donor aspirins. Different amounts of aspirin were released in serum from these products according to the nature of nitrooxyacyloxy moiety present. In the aromatic series, there is a rather good linear correlation between the amount of aspirin released and the potencies of the products in inhibiting platelet aggregation induced by collagen. Both the native compounds and the related nitrooxy-substituted acid metabolites were able to relax rat aorta strips precontracted with phenylephrine, in keeping with a NO-induced activation of the sGC as a mechanism that underlies the vasodilator effect. The products here described are new improved examples of NO-donor aspirins containing nitrooxy groups. They could represent an alternative to the use of aspirin in a variety of clinical applications.

Leishmanicidal Activities of Novel Synthetic Furoxan and Benzofuroxan Derivatives

ABSTRACT A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.

Multitarget drugs: Focus on the NO-donor hybrid drugs

The article addresses the design of multitarget drugs, namely, compounds capable of interacting with more than one target simultaneously. These agents could be useful tools in the therapy of complex diseases such as cardiovascular and inflammatory diseases. An interesting case of multitarget compounds are nitric oxide (NO)-donor hybrids, structures which combine the physiological properties of NO with those of a lead drug. In particular, the authors discuss the symbiotic approach used to design NO-donor nonsteroidal anti-inflammatory drugs (NO-NSAIDs) and NO-donor antioxidants. The former could be useful agents in the treatment of anti-inflammatory diseases being devoid of gastro- and cardiotoxicity, the latter could be a valid approach to the treatment of many cardiovascular diseases.

Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

Novel antioxidant agents deriving from molecular combination of Vitamin C and NO-donor moieties

In this paper, we describe a new class of products in which NO-donor moieties are linked to either the 3-OH (4a-f) or 2-OH group (7a-c) of ascorbic acid (ASA). Log Ps and pK(a)s of these products were experimentally evaluated. All the compounds were tested for their antioxidant activity on lipidic peroxidation induced by Fe(3+)-ADP/NADPH in lipids of microsomal membranes of rat hepatocytes. Only 3-O series displays antioxidant activity and it seems to be principally dependent on the lipophilicity. Both series trigger in vitro NO-dependent vasodilator properties.