SPECIFICITY OF INTERACTION OF SPECIFICITY OF INTERACTION OF HYDROCHLOROTHIAZIDE AND ITS N-NITROSO HYDROCHLOROTHIAZIDE AND ITS N-NITROSO

DERIVATIVE WITH 18-MEMBERED MACROCYCLIC DERIVATIVE WITH 18-MEMBERED MACROCYCLIC RECEPTORSRECEPTORS

Gheorghe Duca, Marina Fonari, Eduard Ganin, Gheorghe Duca, Marina Fonari, Eduard Ganin,

Arkadii Yavolovskii, Arkadii Yavolovskii, Yurii SimonovYurii Simonov

Academy of Sciences of R. Moldova, bd St. cel Mare, 1 Chisinau, MoldovaAcademy of Sciences of R. Moldova, bd St. cel Mare, 1 Chisinau, Moldova

Institute of Applied Physics Academy of Sciences of R. Moldova, Institute of Applied Physics Academy of Sciences of R. Moldova, simonov.xray@phys.asm.md

Odessa State Environmental University, Odessa, UkraineOdessa State Environmental University, Odessa, Ukraine

A .V. Bogatsky Physico-Chemical Institute, NAS, Odessa, UkraineA .V. Bogatsky Physico-Chemical Institute, NAS, Odessa, Ukraine

Content: Content:

IntroductionIntroduction

Recognition in the system crown ether – biologically Recognition in the system crown ether – biologically important molecule / drug :important molecule / drug :

- Thionicotinamide Thionicotinamide

- PP-aminobenzoic acid -aminobenzoic acid

- Oxyproline/ N-nitrosooxyproline Oxyproline/ N-nitrosooxyproline

- Hydrochlorothiazide Hydrochlorothiazide / N-nitroso/ N-nitrosohydrochlorothiazidehydrochlorothiazide

This year, 2007, marks two special anniversaries in the field of Supramolecular Chemistry. Firstly, it is the fortieth anniversary of the publication in the Journal of the American Chemical Society of the synthesis and cation binding properties

of crown ethers by Charles J. Pedersen.

In 1987, the trailblazing work of Donald J. Cram, Jean-Marie Lehn (who coined the term ‘Supramolecular Chemistry’) and Charles J. Pedersen was recognised

by the award of the Nobel Prize in Chemistry ‘‘for their development and use of molecules with structure specific interactions of high selectivity’’ and it is the twentieth anniversary of this special event that is also marked by this issue of

Chemical Society Reviews.

Philip A. Gale Supramolecular chemistry anniversary, Chem. Soc. Rev., 2007, 36, 141–142

Milestone EventsMilestone Events

1967 - Pedersen's 'blockbuster' paper reported discovery of crown ethers and their complexes

Ch. J. Pedersen Cyclic Polyethers and Their Complexes with Metal Salts JACS, 1967, V.89, 7017

1983 - Elbasyouny A., et al., Host-Guest Complexes of Crown Ethers with Neutral Molecules Possessing the Structure Element XH2 (X=O,N,C)

JACS, 1983, V.105, 6568Watson et al., Host-Guest Complex Chemistry. Structures of 18-Crown-6 and

Diaza-18-Crown-6 with Neutral Molecules J. Org. Chem. 1984, V.49, 347

2004 - G.W. Gokel, W.M. Leevy, M.E. Weber, Crown Ethers: Sensors for Ions and Molecular Scaffolds for Materials and Biological Models

Chem. Rev. 2004, 104, 2723-2750

2007 - G.W. Gokel & I.A. Carasel, Biologically active, synthetic ion transporters Chem. Soc. Rev., 2007, 36, 378–389

Cambridge Structural Database: 1500 hits with 18-crown-6 molecule

……One approach is to prepare structures that are designed to mimic or probe One approach is to prepare structures that are designed to mimic or probe specific chemical interactions thought to be involved in biological function. specific chemical interactions thought to be involved in biological function.

……A different approach involves the preparation of simplified models that A different approach involves the preparation of simplified models that function in the same way as a biologically important structure. function in the same way as a biologically important structure.

……Crown ether compounds have played a role in both approachesCrown ether compounds have played a role in both approaches.

G.W. Gokel et al., Chemical Reviews, 2004

Recognition in the system crown ether – Recognition in the system crown ether –

biologically important molecule / drugbiologically important molecule / drug

Recognition in the system crown ether – Recognition in the system crown ether –

biologically important molecule / drugbiologically important molecule / drug

Crown ethers as model systems have distinct advantages over the native Crown ethers as model systems have distinct advantages over the native biological macromolecules that conclude biological macromolecules that conclude in the relative simplicity of an in the relative simplicity of an appropriate model system allows for specific interactions to be isolated and appropriate model system allows for specific interactions to be isolated and studiedstudied in the absence of many others that present in biological in the absence of many others that present in biological macromolecules. macromolecules.

Classic OClassic Ocontaining crown ethers, acting exclusively as the collective containing crown ethers, acting exclusively as the collective hydrogen acceptorshydrogen acceptors, permit to pick up exclusively the C, permit to pick up exclusively the CH, NH, NH, or OH, or OHH……

O(crown) hydrogen-bonding component and estimate its contribution into the O(crown) hydrogen-bonding component and estimate its contribution into the overall system of interactions with the biologically important molecules. overall system of interactions with the biologically important molecules.

System crown ether System crown ether thionicotinamide (TNA) thionicotinamide (TNA)

Association of thionicotinamide Association of thionicotinamide molecules in the pure formmolecules in the pure form

18C6 : TNA, 18C6 : TNA, 1 :1 1 :1

B18C6 : TNA, B18C6 : TNA, 1 :1 1 :1

Cis-anti-cis-Cis-anti-cis-DCH18C6 : TNA : DCH18C6 : TNA : water, 1 : 2 : 1water, 1 : 2 : 1

J. Mol. Str., 2006J. Mol. Str., 2006

System crown ether System crown ether pp-aminobenzoic acid (PABA)-aminobenzoic acid (PABA)Molecular complexes of PABAMolecular complexes of PABA

Supramol. Chem., 1994Supramol. Chem., 1994

CSD data: two PABACSD data: two PABA p polymorphs distinctive by the H-bonding organisationolymorphs distinctive by the H-bonding organisation

Cis-anti-cis-Cis-anti-cis-DCH18C6 : PABA, 1 : 2DCH18C6 : PABA, 1 : 2 Cis-syn-cis-Cis-syn-cis-DCH18C6 : PABA, 1 : 2DCH18C6 : PABA, 1 : 2

System crown ether System crown ether pp-aminobenzoic acid (PABA)-aminobenzoic acid (PABA)Proton-transfer complexes of PABAProton-transfer complexes of PABA

1:2:2 sp. gr. P21/c

1:2:1, sp. gr. C2/c1:2:2, sp. gr. P21

2:2:3, sp. gr. P21 1:2:2, sp. gr. Pc 1:1:3 sp. gr. Pca21

New J. Chem., 2007; Acta Cryst., 2006New J. Chem., 2007; Acta Cryst., 2006

ConclusionsConclusions

The supramolecular synthesis of the PABA - macrocycle complexes in a The supramolecular synthesis of the PABA - macrocycle complexes in a water-methanol solution unambiguously leads to hydrated salts. The number of water-methanol solution unambiguously leads to hydrated salts. The number of

PABA anions in the complex equals to the number of N-protonated binding sites PABA anions in the complex equals to the number of N-protonated binding sites in the cyclic molecule. in the cyclic molecule.

The proton transfer within the complex seems to be a favorable factor for The proton transfer within the complex seems to be a favorable factor for aquation, while in the case of the less polar classic O-containing crown ethers aquation, while in the case of the less polar classic O-containing crown ethers

the anhydrous adducts have been obtained.the anhydrous adducts have been obtained.

Survey of the hydrogen-bonding arrays easily reveals the significant role of Survey of the hydrogen-bonding arrays easily reveals the significant role of water molecules to balance the number of proton-donor and proton-acceptor water molecules to balance the number of proton-donor and proton-acceptor sites involved in the intermolecular hydrogen bonding interactions. Thus, the sites involved in the intermolecular hydrogen bonding interactions. Thus, the reported crystal structures obviously show the important glue water function reported crystal structures obviously show the important glue water function

that serves as an intermediate between the supramolecular reagents. that serves as an intermediate between the supramolecular reagents.

Nitrosation of biologically important moleculesNitrosation of biologically important molecules

The micro–organisms, isolated from the human gastro–intestinal tract, are capable to catalyse Nnitrosation of medicinal drugs and other compounds resulting in carcinogenic derivatives. From chemical point of view, the nitrosation of amines is possible by two ways, by the endogenous nitrogen oxide (NO) in the conditions of the oxidation reaction and by exogenous nitrites in the acidic medium. The typical reagents for this reaction are sodium nitrite and aqueous solutions of hydrochloric HCl or sulfuric H2SO4 acids (this mixture

yields nitrous acid, HNO2). The actual nitrosation reagent is the nitrosyl cation, NO+ which is

formed in situ. The nature of the product depends on the nature of the initial amine. Secondary alkyl or aryl amines yield N–nitrosoamines

Oxyproline/ Oxyproline/ N-N-nitrosooxyprolinenitrosooxyproline

As the only amino acids with the imino group, L-Proline (Pro) and 4(R)-hydroxy-L-proline (Hyp) were extensively studied to elucidate the conditions responsible for the generation of carcinogenic N-nitrosoderivatives. The nitrosation of 4-hydroxy-L-proline (Hyp) by butylnitrite in the acidic medium has been fulfilled and the crystal structure of N-nitroso-derivative, 4-hydroxy-1-nitrosopyrrolidine-2-carboxylic acid 1, was studied by X-ray crystallography.

(4R)-4-Hydroxy-1-nitroso-L-prolineTetrahedron, 2006; a 7.644(2) b 8.849(3) c 10.303(3), P212121, R = 3.09

HOPROL12 - 4-Hydroxy-L-proline (zwitter-ion)T.F.Koetzle et al., Acta Crystallogr., B, 1973; a 4.995(3) b 8.307(3) c 14.193(5), P212121, R = 3.2

Oxyproline/ Oxyproline/ N-N-nitrosooxyprolinenitrosooxyproline

3D network3D network 2D sheet2D sheet

System crown ether System crown ether Hydrochlorothiazide Hydrochlorothiazide / N-/ N-nitrosonitrosohydrochlorothiazidehydrochlorothiazide

18C6 18C6 hydrochlorothiazide hydrochlorothiazideHead-to-tail coordination,Head-to-tail coordination,

1:1 ratio 1:1 ratio

Kristallografiya, Kristallografiya, 19901990

18C6 18C6 NN--nitrosohydrochlorothiazidenitrosohydrochlorothiazide

Head-to-head coordination, Head-to-head coordination, 1:2 ratio1:2 ratio

Tetrahedron,Tetrahedron, 2005 2005

18C6 18C6 hydrochlorothiazide (1:1) hydrochlorothiazide (1:1)18C6 18C6 NN-nitrosohydrochlorothiazide (1:2)-nitrosohydrochlorothiazide (1:2)

Supramolecular organisationSupramolecular organisation

Alternative chainAlternative chain

RibbonRibbon

Cis-anti-cis-Cis-anti-cis-DCH18C6 : hydrochlorothiazide (1:2)DCH18C6 : hydrochlorothiazide (1:2)

Cis-anti-cis-Cis-anti-cis-DCH18C6 : DCH18C6 : NN-nitrosohydrochlorothiazide (1:2)-nitrosohydrochlorothiazide (1:2)

TetrahedronTetrahedron, 2005, 2005

Supramol. Chem., 1995Supramol. Chem., 1995

ConclusionsConclusions

The widely used diuretic, 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-The widely used diuretic, 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, hydrochlorothiazide (HCTZ), was treated by sodium sulfonamide-1,1-dioxide, hydrochlorothiazide (HCTZ), was treated by sodium nitrite under acidic conditions (imitating the conditions of gastric juice). The nitrite under acidic conditions (imitating the conditions of gastric juice). The potential carcinogenic derivative, N-nitrosohydrochlorothiazide (O=N-HCTZ) potential carcinogenic derivative, N-nitrosohydrochlorothiazide (O=N-HCTZ) was obtained and its binding mode with two artificial macrocyclic receptors, was obtained and its binding mode with two artificial macrocyclic receptors, 18-crown-6 and 18-crown-6 and cis-anti-ciscis-anti-cis dicyclohexyl-18-crown-6 was compared with HCTZ. dicyclohexyl-18-crown-6 was compared with HCTZ.

In the case of a flexible and high-responsible 18-crown-6, the change in the In the case of a flexible and high-responsible 18-crown-6, the change in the substrate-receptor interaction is dictated by the prohibition of the secondary substrate-receptor interaction is dictated by the prohibition of the secondary amino-group of O=N-HCTZ in NHamino-group of O=N-HCTZ in NH……O(crown) interactions, while in the case of O(crown) interactions, while in the case of its substituted analogue DCH6B, the steric impediments of cyclohexyl units its substituted analogue DCH6B, the steric impediments of cyclohexyl units appear to be decisive and namely they exclude the participation of the appear to be decisive and namely they exclude the participation of the secondary amino group of HCTZ in the interactions with crown ether, so the secondary amino group of HCTZ in the interactions with crown ether, so the nitrosation of this group does not influence the overall mode of HCTZ/O=N-nitrosation of this group does not influence the overall mode of HCTZ/O=N-HCTZ – DCH6B interaction. HCTZ – DCH6B interaction.

The interest in crown ethers in both biological science and industry is keen The interest in crown ethers in both biological science and industry is keen and growing. and growing.

Crowns have demonstrated significance in the catalysis of reactions that use Crowns have demonstrated significance in the catalysis of reactions that use enzymes in organic solvents. enzymes in organic solvents.

Functionalized crowns have also been synthesized to bind and cleave DNA Functionalized crowns have also been synthesized to bind and cleave DNA and have led to investigative drug studies in cancer research. Furthermore, and have led to investigative drug studies in cancer research. Furthermore,

crown compounds are being developed to fight microbial resistance. crown compounds are being developed to fight microbial resistance. Without question, crown ethers have a firm foundation in biological science Without question, crown ethers have a firm foundation in biological science and industry that will produce new and innovative applications with future and industry that will produce new and innovative applications with future

generations of compounds.generations of compounds.

The application of these remarkable compounds shows no obvious limit… The application of these remarkable compounds shows no obvious limit…  

G. W. Gokel et al., G. W. Gokel et al., Chem. Rev. Chem. Rev. 2004, 2004, 104, 104, 2723-27502723-2750