Prototropic Properties Research Articles

PH assisted modulation in the binding affinity for BODIPY-benzimidazole conjugate with anionic cyclodextrin

Modulation in the properties of chromophoric guest dyes involving non-covalent supramolecular interactions of various macrocyclic hosts are the intense topics of current research. In this study we report interaction of a sulfobutylether-β-cyclodextrin (SBEβCD) host in modulating the photophysical as well as prototropic properties of an inhouse synthesized BODIPY-benzimidazole conjugate dye, abbreviated as BDZ. The SBEβCD host displays substantially different binding strengths for the protonated and unprotonated forms of the prototropic BDZ dye, inducing a large upward pKa shift for the dye. Furthermore, structural confinement of the dye upon binding with the host leads to substantial enhancement in the fluorescence intensity and lifetime for both the prototropic forms of the dye. This can be attributted to the reduction in the non-radiative deexcitation process for the bound dye. Fluorescence enhancements are also accompanied with large increase in fluorescence anisotropy decay times, substantiating dye-host binding. Since unprotonated BDZ in free state is extremely weak in emission due to its intramolecular charge transfer (ICT) character, its fluorescence enhancement on binding to SBEβCD is found to be more pronounced than protonated BDZ. Importantly, emission of BDZ–SBEβCD system appears in the green region of visible spectrum, implying the immense prospect of the system for fluorescence-based sensor and imaging applications in different biological studies.

Multi PCET in symmetrically substituted benzimidazoles.

Proton-coupled electron transfer (PCET) reactions depend on the hydrogen-bond connectivity between sites of proton donors and acceptors. The 2-(2′-hydroxyphenyl) benzimidazole (BIP) based systems, which mimic the natural TyrZ-His190 pair of Photosystem II, have been useful for understanding the associated PCET process triggered by one-electron oxidation of the phenol. Substitution of the benzimidazole by an appropriate terminal proton acceptor (TPA) group allows for two-proton translocations. However, the prototropic properties of substituted benzimidazole rings and rotation around the bond linking the phenol and the benzimidazole can lead to isomers that interrupt the intramolecular hydrogen-bonded network and thereby prevent a second proton translocation. Herein, a strategic symmetrization of a benzimidazole based system with two identical TPAs yields an uninterrupted network of intramolecular hydrogen bonds regardless of the isomeric form. NMR data confirms the presence of a single isomeric form in the disubstituted system but not in the monosubstituted system in certain solvents. Infrared spectroelectrochemistry demonstrates a two-proton transfer process associated with the oxidation of the phenol occurring at a lower redox potential in the disubstituted system relative to its monosubstituted analogue. Computational studies support these findings and show that the disubstituted system stabilizes the oxidized two-proton transfer product through the formation of a bifurcated hydrogen bond. Considering the prototropic properties of the benzimidazole heterocycle in the context of multiple PCET will improve the next generation of novel, bioinspired constructs built by concatenated units of benzimidazoles, thus allowing proton translocations at nanoscale length.

In situ reactivity of electrochemically generated semiquinone on Emodin and its CuII/MnII complexes with pyrimidine based nucleic acid bases and calf thymus DNA: Insight into free radical induced cytotoxicity of anthracyclines

There is enough proof to believe that free-radical intermediates of anthracycline based anticancer agents are involved in different stages of drug action. Subtle therapeutic differences observed in the actions of different anthracyclines largely influence the mechanism of action of the drugs that distinguish one member from another. Redox properties control biological responses related either to the one-electron quinone/semiquinone couple or the two-electron quinone/quinone-dianion couple. Comproportionation also leads to generation of semiquinone. Hence, whatever the form of reduction of the quinone moiety, a substantial amount of semiquinone is eventually formed in the system. Immediately after formation, there is competition between natural radical-decay pathways and one-electron transfer reactions that generate the superoxide-radical anion. Prototropic properties control rate of radical decay while redox properties control rate of electron transfer to molecular oxygen. In aerated medium, semiquinone-radical anion and superoxide-radical anion co-exist while in de-aerated medium semiquinone-radical anion predominates. All the radicals are damaging to the biological system. Through this study, attempt was made to detect changes induced by the radicals on pyrimidine based nucleic acid bases and calf thymus DNA in aerated and de-aerated (Ar saturated) medium to know the mechanism by which Emodin, its CuII/MnII complexes might affect DNA. Semiquinone-radical anion was generated electrochemically maintaining a glassy carbon electrode at the first reduction potential of each compound. Since the chosen compound (Emodin), its complexes are analogues of anthracyclines, findings on them can be extrapolated to understand the differences in anticancer activity or of adverse drug reactions reported in an innumerable number of clinical studies related to anthracyclines where the difference in structure of different members is due to differences in the relative positioning of hydroxy groups on the hydroxy-9, 10-anthraquinone moiety of anthracyclines. The study helps to realize action of compounds of this class as anticancer agents.

Hydroxybenzo[b]quinolizinium Ions: Water-Soluble and Solvatochromic Photoacids.

It is shown by photometric and fluorimetric analysis, along with supporting theoretical calculations, that hydroxy-substituted benzo[b]quinolizinium derivatives display the characteristic features of organic photoacids. Specifically, the experimental and theoretical results confirm the strong acidity of these compounds in the excited state (pKa* < 0). The combination of the prototropic properties of 8- and 9-hydroxybenzo[b]quinolizinium with the particular solvent-solute interactions of the excited acid and its conjugate base leads to a pronounced fluorosolvatochromism, hence the emission maxima shift from 468 nm (8-hydroxybenzo[b]quinolizinium) or 460 nm (9-hydroxybenzo[b]quinolizinium) in CH3CN to 507 and 553 nm in DMF, respectively. This novel type of photoacid represents several features that may be used for applications as water-soluble fluorescent probes or as a source for the photoinduced supply of acidity.

Supramolecular host–guest interaction of acridine dye with cyclodextrin macrocycles: Photophysical, pKa shift and quenching study

► Interactions of acridine dye with cyclodextrin hosts have been investigated. ► Host–guest complexes with 1:1 stoichiometry are mainly formed in these systems. ► Complexation with CD causes significant modulations in the photophysical and acid–base properties of the dye. ► Can have implications in host assisted drug stabilization and supramolecular fluorescence probes and sensors. Supramolecular host–guest interaction of acridine dye, a biologically important molecule, with β and γ cyclodextrin (βCD and γCD, respectively) macrocycles has been investigated in aqueous solution using photophysical methods. Neutral form (Ac) of the dye undergoes significant interaction with βCD and γCD hosts, forming mainly the 1:1 stoichiometric host–guest complex. Fluorescence intensity and lifetime of Ac reduces drastically on binding with CD hosts, ascribed to H-bonding interaction of the portal OH groups of the hosts with bound excited dye. The fraction of the free dye in these systems also shows significant reduction in fluorescence lifetime that displays liner Stern–Volmer correlation, suggesting dynamic quenching of the free dye through similar H-bonding interaction with the portal OH groups of the hosts. Present contention is support by the fluorescence intensity and lifetime reduction of the dye on using d -glucose as the quencher. Ac interacts relatively strongly with βCD than γCD, attributed to tighter binding of the dye with smaller βCD cavity than larger γCD cavity. The inclusion complex formation in the present Ac–CD systems is suitably supported by time-resolved fluorescence anisotropy results. Unlike neutral Ac form, the protonated AcH + form of the dye does not show any significant interaction with either βCD or γCD hosts. The differential interaction of Ac and AcH + forms with the CDs results in the downward p K a shifts for the dye by ∼0.43 and ∼0.32 units, respectively, in the presence of 16 mM βCD and 40 mM γCD (4) hosts. Since CD concentrations much higher than these could not be used due to their solubility limitations and hence the condition of complete complexation for both Ac and AcH + forms with CD hosts could not be achieved in these solutions, the above p K a shifts are certainly the apparent ones, and the true p K a shifts for the complexed dye would have been significantly higher than the above values. In any case, the observed p K a shifts in the present study is the first report on the macrocyclic host induced changes in the prototropic properties of acridine dye. Observed modulations in the photophysics and acid–base properties of acridine dye reported here can have a bearing to the host assisted drug stabilization and supramolecular fluorescence probes and sensors.

Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides

Revealing the free radical mechanism by which the anticancer drug tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) induces hypoxia-selective cytotoxicity, is seen as a way forward to develop clinically useful bioreductive drugs against chemo- and radiation-resistant hypoxic tumor cells. Our previous studies point to the formation of an active benzotriazinyl radical following the one-electron reduction of tirapazamine and its elimination of water from the initial reduction intermediate, and have suggested that this species is a cytotoxin. In this paper we have used pulse radiolysis to measure the one-electron reduction potentials of the benzotriazinyl radicals E(B*,H(+)/B) of 30 analogues of tirapazamine as well as the one-electron reduction potentials of their two-electron reduced metabolites, benzotriazine 1-oxides E(B/B*-). The redox dependencies of the back-oxidation of the one-electron reduced benzotriazine 1,4-dioxides by oxygen, their radical prototropic properties and water elimination reactions were found to be tracked in the main by the one-electron reduction potentials of the benzotriazine 1,4-dioxides E(A/A*-). Multiple regression analysis of published aerobic and hypoxic clonogenic cytotoxicity data for the SCCVII murine tumor cell line with the physical chemistry parameters measured in this study, revealed that hypoxic cytotoxicity is dependent on E(B*, H(+)/B) thus providing strong evidence that the benzotriazinyl radicals are the active cytotoxic species in hypoxia, while aerobic cytotoxicity is dependent on E(B/B*-). It is concluded that maximizing the differential ratio between these two controlling parameters, in combination with necessary pharmacological aspects, will lead to more efficacious anticancer bioreductive drugs.

Acid–base chemistry of omeprazole in aqueous solutions

Omeprazole is a potent anti-acid drug. Its absorption and mode of action are closely related to its prototropic behavior. In the present study, omeprazole samples from different sources and in different forms were studied spectrophotometrically to obtain p K a values. In the neutral to alkaline pH region, two consistent p K a values of 7.1 and 14.7 were obtained from various samples. The assignment of these p K a values was realized by comparison with the prototropic properties of N(1)-methylated omeprazole substituted on the nitrogen at the 1-position of the benzimidazole ring, which was found to have a p K a of 7.5. The omeprazole p K a of 14.7 is assigned to the dissociation of the hydrogen from the 1-position of the benzimidazole ring and the p K a of 7.1 is assigned to the dissociation from the protonated pyridine nitrogen of omeprazole. The results presented are at variance with those of earlier work.

Proton transfer and coordination properties of aromatic α-hydroxy hydrazones

The prototropic properties of two nitro derivatives of aromatic α-hydroxy hydrazones [2,4-dinitro- N-phenyl- N′(2-hydroxy-1-phenylmethylene hydrazine) and 2,4-dinitro- N-phenyl- N′(2-hydroxy-1-naphthylmethylene hydrazine] have been analysed through electronic absorption, 1H and 13C NMR and semiempirical molecular orbital methods. The metal binding properties of both compounds and of the unsubstituted hydrazones were evaluated from potentiometric and spectrophotometric data in dioxane–water mixtures. On the basis of the spectral analysis and PM3 semiempirical calculations, the structures of the formed complexes were proposed.

Cu(II), Ni(II) and Co(II) co-ordination properties and tautomerism of 1,8-bis-phenylazo-2,7-dihydroxy naphthalene. A spectroscopic and semiempirical AM1/PM3 study

As a continuation of a study on the prototropic properties of aromatic α,α′-dihydroxy-bis-azocompounds, 1,8-bis-phenylazo-2,7-dihydroxynaphthalene (PHADN) has been studied through 1H and 13C nuclear magnetic resonance experiments, electronic absorption and semiempirical molecular orbital methods. In addition, the metal binding properties of this compound were evaluated and related with its tautomeric forms. The equilibrium constants for Cu(II), Ni(II) and Co(II)–PHADN complexes were spectrophotometrically determined in dioxane–water 50% v/v solutions. The structures of the evaluated chelates were proposed on the basis of spectral analysis and PM3 semiempirical calculations.

Interaction Between Phosphoric Anhydride and Organic Compounds with Prototropic Properties

Abstract: Phosphoric anhydride has been shown to interact with organic compounds with prototropic properties, i.e. unsubstituted and monosubstituted amides, pyrimidinetriones, azoles and esters. Some products of phosphorylation have a tendency to exhibit phosphorotropy (1-3 and 1-4 shifts).

Exploring Reactions of Nucleoside H-Phosphonates with Bifunctional Reagents

Abstract: Phosphoric anhydride has been shown to interact with organic compounds with prototropic properties, i.e. unsubstituted and monosubstituted amides, pyrimidinetriones, azoles and esters. Some products of phosphorylation have a tendency to exhibit phosphorotropy (1-3 and 1-4 shifts).

Interaction Between Phosphoric Anhydride and Organic Compounds with Prototropic Properties

Abstract: Phosphoric anhydride has been shown to interact with organic compounds with prototropic properties, i.e. unsubstituted and monosubstituted amides, pyrimidinetriones, azoles and esters. Some products of phosphorylation have a tendency to exhibit phosphorotropy (1-3 and 1-4 shifts).

Exploring Reactions of Nucleoside H-Phosphonates with Bifunctional Reagents

Abstract: Phosphoric anhydride has been shown to interact with organic compounds with prototropic properties, i.e. unsubstituted and monosubstituted amides, pyrimidinetriones, azoles and esters. Some products of phosphorylation have a tendency to exhibit phosphorotropy (1-3 and 1-4 shifts).

Control of the generation and reactions of free radicals in biological systems by kinetic and thermodynamic factors.

Quantifiable redox properties are useful predictors of substrate reactivity in enzyme-catalysed redox reactions of e.g. nitroreductases or peroxidases. Redox properties may also control the rates of electron-transfer reactions between radical products of reduction and oxidation, and endogenous oxidants and reductants respectively. However, in numerous instances prototropic properties of substrate or radical may have profound kinetic consequences, protonation of radicals frequently slowing down electron-transfer reactions. Further, reactions which are thermodynamically extremely unfavourable may still proceed if radical products are removed from the pre-equilibrium efficiently. Thus kinetic considerations often outweigh the purely thermodynamic viewpoint.

A comparison of tumor and normal tissue levels of acidic, basic and neutral 2-nitroimidazole radiosensitizers in mice

Pharmacokinetic studies were carried out in mice after co-administration of 2-nitroimidazoles with differing prototropic properties: Ro 03-8799, misonidazole, SR 2508, and azomycin. In addition, the distribution of sensitizers in different areas of individual tumors, as well as several normal tissues were measured after intravenous dosing of 0.5 mmol kg −1 (145-56 mg/kg). Although there appeared to be no significant pharmacokinetic interaction between sensitizers after co-administration, there was a significant difference in the distribution of sensitizers within tumors of differing type and size. In small, fast growing SaFa and large, slow growing CaRH tumors, the levels of all sensitizers was relatively constant throughout. However, large fast growing SaFa tumors demonstrated the high degree of variability in the Ro 03-8799 concentration that is seen in the clinic. This may be important in the modelling of human tumors with regard to sensitizer distribution.

Mitomycin antitumour agents: A review of their physico-chemical and analytical properties and stability

The review enumerates the physico-chemical and analytical properties of mitomycin antitumour antibiotics, of which mitomycin C is the most important representative. After a short overview of the position of the compounds in oncology the following subjects will be discussed: structural features, prototropic properties, spectroscopy (UV-VIS, ORD, CD, IR, NMR, MS), chromatography and electrochemistry. The chemical stability and aspects of the mechanism of action of the compounds are also discussed. The last part of the review surveys the analysis of mitomycin C in biological fluids.

Some Reactions and Properties of Nitro Radical-Anions Important in Biology and Medicine

Nitroaromatic compounds, ArNO2 have widespread actual or potential use in medicine and cancer therapy. There is direct proof that free-radical metabolites are involved in many applications, and an appreciation of the conceptual basis for their therapeutic differential; however, an understanding of the detailed mechanisms involved is lacking. Redox properties control most biological responses of nitro compounds, and the characteristics of the one-electron couple: ArNO2/ArNO2- are detailed. The "futile metabolism" of nitroaryl compounds characteristic of most aerobic nitroreductase systems reflects competition between natural radical-decay pathways and a one-electron transfer reaction to yield superoxide ion, O2-. Prototropic properties control the rate of radical decay, and redox properties control the rate of electron transfer to O2 or other acceptors. There are clear parallels in the chemistry of ArNO2- and O2-. While nitro radicals have frequently been invoked as damaging species, they are very unreactive (except as simple reductants). It seems likely that reductive metabolism of nitroaryl compounds, although generally involving nitro radical-anions as obligate intermediates (and this is required for therapeutic selectivity towards anaerobes), results in biological damage via reductive metabolites of higher reduction order than the one-electron product.

Determination of pKa Values of Some Prototropic Functions in Mitomycin and Porfiromycin

The prototropic properties of mitomycin and porfiromycin were studied. pK0 values for two potentially basic groups and one acidic function could be established by titration. The kinetics of the tautom- erization preceding the prototropic reaction in an alkaline medium were investigated.