Carbonic anhydrase inhibitors. Regioselective synthesis of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII

doi:10.1016/j.ejmech.2010.05.011

European Journal of Medicinal Chemistry

Volume 45, Issue 9, September 2010, Pages 3656-3661

https://doi.org/10.1016/j.ejmech.2010.05.011 Get rights and content

Abstract

A series of 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamide (2–16) have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic ubiquitous CA I and II, and cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed inhibition constants in the range of 1.09–12.1 μM, against hCA II in the range of 50.5–172 nM, against hCA IX in the range of 5.2–118 nM, and against hCA XII in the range of 8.7–381 nM, respectively. Compounds 2, 3, 5–9, 11, 13 and 14 showed excellent hCA IX inhibitory efficacy, with K_Is = 5.2–11.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (K_Is = 24–50 nM). Compounds 2, 3, 5–9, 11 and 13 were also very effective hCA XII inhibitors (K_Is = 8.7–45.2 nM) which are comparable or more effective than those clinically used EZA and DCP (K_Is = 22 and 50 nM), respectively.

Graphical abstract

A novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides have been synthesized and investigated as inhibitors of carbonic anhydrase isozymes hCA I, II, IX and XII. Some of them showed excellent hCA IX and XII inhibitory efficacy.

Introduction

The carbonic anhydrases (CAs, EC 4.2.1.1) [1], [2], [3], [4] constitute interesting targets for the design of pharmacological agents useful in the treatment or prevention of a variety of disorders such as glaucoma, acid-base disequilibria, epilepsy and other neuromuscular diseases, altitude sickness, edema, and obesity [5], [6]. A quite new and unexpected application of the CA inhibitors (CAIs) regards their potential use in the management (imaging and treatment) of hypoxic tumors [7], [8], [9], [10], [11], [12], [13], [14], since at least two CA isozymes of the 15 presently known in humans, that is CA IX and XII, are predominantly found in tumor cells and lack (or are present in very limited amount) in normal tissues [15], [16], [17], [18]. The potential use of CAIs as antitumor agents opens thus a new important research direction [19], [20].

Recently, we have reported on the strong inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with some S-substituted 4-chloro-5-or 6-methylbenzenesulfonamides I and II [21], [22], [23] (Chart 1). We also described the syntheses a number of 4-substituted 3-pyridinesulfonamides of type III (Chart 1), and their inhibitory activities against human isozymes hCA I, II, IX, XII and XIV [24]. Some of these compounds exhibited excellent hCA IX inhibitory efficacy, with inhibition constants of 4.6–12.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (in clinical development drug). These findings prompted us to synthesize and investigate of the related 3-pyridinesulfonamides of type IV (Chart 1).

Section snippets

Chemistry

The previously described method was applied to the synthesis of 4-methoxy-3-pyridinesulfonamide 1 [24]. The synthesis of the target 1,4-dihydro-4-oxo-3-pyridinesulfonamides 2–15 were achieved with yields in the 59–97% range by a convenient one-step procedure starting from 4-methoxy-3-pyridinesulfonamide 1 and the appropriate activated aliphatic or aromatic halides in dry acetonitrile. The proposed mechanism leading to the formation of the products 2–15 is outlined in Scheme 1, Scheme 2. The

Conclusions

We have developed methods for the regioselective synthesis of 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides. The fourteen new sulfonamide have been assayed for the inhibition of four physiological relevant CA isozymes, such as CA I and II, and the tumor-associated isozymes CA IX and XII. Against the human isozyme hCA I the new sulfonamide showed inhibition constants in the range of 1.09–14.2 μM; against hCA II in the range 50.5–172 nM, against hCA IX in the range 5.2–96 nM, and against

Synthesis

The following instruments and parameters were used: melting points Bűchi 535 apparatus; IR spectra: KBr pellets, 400–4000 cm⁻¹ Perkin Elmer 1600 FTIR spectrometer; ¹H and ¹³C NMR: Varian Gemini 200 apparatus at 200 and 50 MHz, respectively; chemical shifts are expressed in parts per million (ppm) relative to TMS as internal standard. The results of elemental analyses for C, H and N were within ±0.4% of theoretical values. The starting 4-methoxy-3-pyridinesulfonamide 1 was prepared according to

Acknowledgments

This research was financed in part by a grant of the 6th Framework Programme of the European Union (DeZnIT project) and by a grant of the 7th FP of EU (Metoxia project) to CTS.

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Original articleCarbonic anhydrase inhibitors. Regioselective synthesis of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

Synthesis

Acknowledgments

FEBS Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Trends Pharmacol. Sci.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Tetrahedron Lett.

J. Biol. Med.

Bioorg. Med. Chem. Lett.

Nat. Rev. Drug Discov.

Expert Opin. Ther. Pat.

Carbonic anhydrase: catalytic and inhibition mechanisms, distribution and physiological roles

Curr. Chem. Caridiovasc. Hematol. Agents

J. Enzym. Inhibit. Med. Chem.

Expert Opin. Ther. Pat.

Original article
Carbonic anhydrase inhibitors. Regioselective synthesis of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII