Flavin Analogues Research Articles

Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors.

Different classes of compounds were investigated for their binding affinities into different protein tyrosine kinases (PTKs) employing a novel flexible ligand docking approach by using AutoDock 3.05 and 4. These compounds include many flavin analogs, which were developed in our group with varying degrees of cytotoxic activity (comparable or moderately superior to cisplatin and ara-c), and database selected analogs. They were docked onto twelve different families of PTKs retrieved from the Protein Data Bank. These proteins are representatives of plausible models of interactions with chemotherapeutic agents. A comparative study of the intact co-crystallized ligands of various types of PTKs was carried out. Results revealed that the new class of 5-deazapteridine and steroid hybrid compounds VIa,b, and d, and the vertical-type bispyridodipyrimidine with n-hexyl chain junction between its N-10 and N-10 atoms Xa, exhibited non-selective PTK binding capacities, with the lowest (Gb). On the other hand, 2-amino benzoic acid analog IIa, phenoxypyrido [3, 4-d]pyrimidine derivative IVc, tyrosine containing tripeptide Vd, and the one from Sumisho data base 831 are proposed to have selective PTK binding affinities to certain classes of tyrosine kinases, namely, HGFR (c-met), ZAP-70, insulin receptor kinase, EGFR, respectively. All These compounds of highest affinities were docked within the binding sites of PTKs with reasonable RMSD and 1-5 hydrogen bonds.

Inter‐ and Intramolecular Photoinduced Electron Transfer of Flavin Derivatives with Extremely Small Reorganization Energies

Photoinduced electron transfer (ET) of a series of aromatic electron donors (D) to the singlet or triplet excited state of a flavin analogue (10-methylisoalloxazine: MeFl) and intermolecular back electron transfer (BET) from MeFl(*-) to D(*+) in benzonitrile (PhCN) has been investigated in light of the Marcus theory of ET. The rate constants of intermolecular photoinduced ET (k(et)) from D to the singlet excited state ((1)MeFl*) and the triplet excited state ((3)MeFl*) were determined by fluorescence quenching and enhanced decay rates of triplet-triplet (T-T) absorption by the presence of D, respectively. The k(et) values increase with an increase in the ET driving force to reach the diffusion-limit value that remains constant with a further increase in the ET driving force. Nanosecond laser flash photolysis was performed to determine the rate constants of intermolecular BET (k(bet)) from MeFl(*-) to D(*+) in PhCN. In contrast to the case of k(et), the driving force dependence of k(bet) shows a pronounced decrease towards the highly exothermic region. The reorganization energy (lambda) of intermolecular BET is determined to be 0.68 eV by applying the Marcus equation in the inverted region, where the k(bet) value decreases with increasing the BET driving force. The slowest BET was observed for BET from MeFl(*-) to N,N-dimethylaniline radical cation (DMA(*+)) with the k(bet) value of 3.5 x 10(6) M(-1) s(-1), which is 1600 times smaller than the diffusion rate constant in PhCN (5.6 x 10(9) M(-1) s(-1)). Then, DMA was linked to the 10-position of isoalloxazine to synthesize a DMA-flavin linked dyad (10-[4'-(N,N-dimethylamino)phenyl]-isoalloxazine: DMA-Fl). Photoexcitation of DMA-Fl results in photoinduced ET from the DMA moiety to the singlet excited state of Fl moiety to form the charge-separated (CS) state (DMA(*+)-Fl(*-)) that has an extremely long lifetime (2.1 ms) in PhCN at 298 K.

ChemInform Abstract: Synthesis of Symmetrical (IV) and Unsymmetrical Alkyl Disulfides (VIII) with Attached Flavin Analogue for Formation of Self-Assembled Monolayers on Gold.

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The Lycopene Cyclase CrtY from Pantoea ananatis (Formerly Erwinia uredovora) Catalyzes an FADred-dependent Non-redox Reaction

The cyclization of lycopene generates provitamin A carotenoids such as beta-carotene and paves the way toward the formation of cyclic xanthophylls playing distinct roles in photosynthesis and as precursors for regulatory molecules in plants and animals. The biochemistry of lycopene cyclization has been enigmatic, as the previously proposed acid-base catalysis conflicted with the possibility of redox catalysis as predicted by the presence of a dinucleotide binding site. We show that reduced FAD is the essential lycopene cyclase (CrtY) cofactor. Using flavin analogs, mass spectrometry, and mutagenesis, evidence was obtained based on which a catalytic mechanism relying on cryptic (net) electron transfer can be refuted. The role of reduced FAD is proposed to reside in the stabilization of a transition state carrying a (partial) positive charge or of a positively charged intermediate via a charge transfer interaction, acid-base catalysis serving as the underlying catalytic principle. Lycopene cyclase, thus, ranks among the novel class of non-redox flavoproteins, such as isopentenyl diphosphate:dimethylallyl diphosphate isomerase type 2 (IDI-2) that requires the reduced form of the cofactor.

A straightforward synthesis of pyrimido[4,5-b]quinoline derivatives assisted by microwave irradiation

Abstract Several pyrimido[4,5-b]quinolines, flavin analogues, have been prepared by assisted microwave intramolecular cyclization of N4-substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes. The reaction takes place with hydrolysis of amino-group and chlorine. Particularly valuable features of this method included the broader substrate scope and operational simplicity as well as increased safety for small-scale high-speed synthesis.

A tetranuclear iridium(iii) complex with a flavin analogue as a bridging ligand in different coordination modes and exchangeable anion encapsulation in a supramolecular cage

A novel tetranuclear Ir(iii) complex involving unprecedented coordination modes of alloxazine formed a closed pi-space by intermolecular hydrogen bonding and the counter anions encapsulated in the space could be exchanged via self-assembly.

Quantitative Electrochemical SERS of Flavin at a Structured Silver Surface

In situ electrochemical surface enhanced Raman spectra (SERS) for an immobilized monolayer of a flavin analogue (isoalloxazine) at nanostructured silver surfaces are reported. Unique in the present study, the flavin is not directly adsorbed at the Ag surface but is attached through a chemical reaction between cysteamine adsorbed on the Ag surface and methylformylisoalloxazine. Even though the flavin is held away from direct contact with the metal, strong surface enhancements are observed. The nanostructured silver surfaces are produced by electrodeposition through colloidal templates to produce thin (<1 microm) films containing close-packed hexagonal arrays of uniform 900 nm sphere segment voids. The sphere segment void (SSV) structured silver surfaces are shown to be ideally suited to in situ electrochemical SERS studies at 633 nm, giving stable, reproducible surface enhancements at a range of electrode potentials, and we show that the SER spectra are sensitive to subfemtomole quantities of immobilized flavin. Studies of the SER spectra as a function of the electrode potential show clear evidence for the formation of the flavin semiquinone at the electrode surface at cathodic potentials.

Photochemical and Thermal Isomerization of a Ruthenium(II)−Alloxazine Complex Involving an Unusual Coordination Mode

A Ru(II) complex having a flavin analogue as a ligand in a unusual coordination mode exhibits a photochemical and thermal isomerization; the bistability of the complex is attained by chelate effect and intramolecular CH···O interaction.

Recognition Properties of Flavin Analogues with Bile Acid-Based Receptors: Role of Steric Effects in Hydrogen Bond Based Molecular Recognition

The recognition properties of 7,8-dimethyl flavin analogues by bile acid-based receptors that contain 2,6-diaminopyridine and the dioctylamide of 2,6-diaminopyridine in CHCl3 were determined. The results show that the bile acid-based receptors bind 7,8-dimethyl flavin analogues less effectively as compared to 7,8-unsubstituted flavins reported earlier, which is contrary to the known fact that the association constants increase with increasing electron-donating capacity of the substituents at the 7 and 8 positions of the flavin analogues.

ルテニウム-トリス（２-ピリジルメチル）アミン錯体の化学

This account describes a current summary of our research on ruthenium complexes having tris(2-pyridylmethyl)amine (TPA) and its derivatives as ligands. Topics include their characteristics, catalytic oxygenations of organic compounds including alkanes, alkenes, and alcohols by peroxide activation and proton-coupled electron transfer to generate Ru(IV)=O complexes as reactive species, Ru-TPA complexes with redox-active heteroaromatic coenzymes such as pterins and flavin analogues to elucidate their characteristics, construction of specific coordination spheres by introducing functional moieties to the TPA ligand via amide linkage to develop non-covalent interactions in the first and second coordination spheres, and bistability in photochromic structural change. The important features of the Ru-TPA complexes are following: (1) Reliable stability due to the π-back bonding from 4dπ orbitals of the ruthenium center to π* orbitals of heteroaromatic ligands, (2) Very clear reversible redox behaviour, (3) Availability of a wide range of oxidation states and a variety of reactivity at the ruthenium center, (4) Feasibility of derivatization of TPA toward the construction of unique coordination environments, and (5) Accessibility to bistability in photochemical and thermal processes.

Antitumor studies – Part 2: Structure–activity relationship study for flavin analogs including investigations on their in vitro antitumor assay and docking simulation into protein tyrosine kinase

Various analogs of flavins, 5-deazaflavins, and flavin-5-oxides were docked into the binding site of protein tyrosine kinase pp60 c-src, and some of them were assayed for their potential antitumor and PKC (protein kinase C) inhibitory activities in vitro. The results considering SAR (structure–activity relationship) revealed that the higher binding affinities obtained include compounds with the structure modifications on the flavin or 5-deazaflavin skeleton, namely, NH 2 or Ph (phenyl-) group at the C-2 position and so on. Computationally designed compounds 4a, 6a, b, 7, 11b, c, 12, 15, and 22c exhibited good docking results suggesting that they are potentially active antitumor agents. These compounds have 1–3 phenyl moieties, which are thought to be responsible for the planar aromatic fitting or electrostatic attraction onto the groove of the binding pocket.

A flavin analogue with improved solubility in organic solvents

We report the synthesis and initial electrochemical characterization of a benzene-soluble flavin analogue: N(10)-2,2-dibenzylethyl-7,8-dimethylisoalloxazine (DBF, 1). This analogue, which has an unmodified flavin headgroup, is intended for use in the spectroscopic examination of the electronic effects of flavin hydrogen bonding in simple model systems in aprotic, non-hydrogen bonding solvents. With future spectroscopic studies in mind, we have developed a synthetic route, which allows the incorporation of isotopic labels using inexpensive starting materials.

Modulation of Characteristics of a Ruthenium‐Coordinated Flavin Analogue That Shows an Unusual Coordination Mode

Hallo− hallo−! An einem Ruthenium(II)-Komplex (1) mit dem Flavinanalogon Alloxazin (H2allo) wurde ein viergliedriger Chelatring des Ligandenanions (Hallo−) nachgewiesen. Diese neuartige Hallo-Koordination ermöglicht zusätzliche Wasserstoffbrücken mit einem komplementären Rezeptor (z. B. 2), was den Einfluss von Wasserstoffbrücken auf das Redoxverhalten und die elektronische Struktur eines rutheniumgebundenen Hallo-Radikals untersuchbar macht.

Modulation of Characteristics of a Ruthenium‐Coordinated Flavin Analogue That Shows an Unusual Coordination Mode

Modulation of Characteristics of a Ruthenium‐Coordinated Flavin Analogue That Shows an Unusual Coordination Mode

Antitumor studies. Part 1: Design, synthesis, antitumor activity, and AutoDock study of 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides as a new class of antitumor agents

Novel 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides were prepared as a new class of antitumor agents and showed significant antitumor activities against NCI-H 460, HCT 116, A 431, CCRF-HSB-2, andKB cell lines. In vivo investigation, 2-deoxo-10-methyl-2-phenyl-5-deazaflavin exhibited the effective antitumor activity against A 431 human adenocarcinoma cells transplanted subcutaneously into nude mouse. Furthermore, AutoDock study has been done by binding of the flavin analogs into PTK pp60 c-src, where a good correlation between their IC 50 and AutoDock binding free energy was exhibited. In particular, 2-deoxo-2-phenylflavin-5-oxides exhibited the highest potential binding affinity within the binding pocket of PTK.

Synthesis and binding ability of bile acid-based receptors for recognition of flavin analogues

Novel cholaphanes 6a, b, based on lithocholic and deoxycholic acids, were synthesised through 3a, b by a sequence of reactions involving Cs-salt methodology of macrocyclisation. Cholaphanes 6a, b and acyclic steroidal receptors 3a, b bind flavin analogues via three hydrogen bonds in CHCl 3.

New photochemically stable riboflavin analogue—3-Methyl-riboflavin tetraacetate

Spectroscopic and photophysical properties of a flavin analogue – 3-methyl-riboflavin tetraacetate – were studied in methanol, ethanol, water and acetonitrile. We compared experimental spectroscopic data with the results of theoretical predictions, obtained using the TD-DFT method. Based on these calculations, we assigned (π,π *) symmetry to both the lowest excited singlet and triplet states. We found the title compound to be a very efficient photosensitizer of singlet oxygen production ( ϕ Δ = 0.61). The triplet state quantum yield of 3-methyl-riboflavin tetraacetate was determined as 0.54 in methanolic solutions. Photodegradation quantum yield measurements demonstrate that the title compound may be used as a much more stable substitute of riboflavin, being two orders of magnitude more photostable ( φ R = 2 × 10 −5). We also present exhaustive crystallographic characteristics of 3-methyl-riboflavin tetraacetate, along with time-resolved fluorescence spectra of its polycrystals.

Riboflavin analogs and inhibitors of riboflavin biosynthesis

Flavins are active components of many enzymes. In most cases, riboflavin (vitamin B(2)) as a coenzyme represents the catalytic part of the holoenzyme. Riboflavin is an amphiphatic molecule and allows a large variety of different interactions with the enzyme itself and also with the substrate. A great number of active riboflavin analogs can readily be synthesized by chemical methods and, thus, a large number of possible inhibitors for many different enzyme targets is conceivable. As mammalian and especially human biochemistry depends on flavins as well, the target of the inhibiting flavin analog has to be carefully selected to avoid unwanted effects. In addition to flavoproteins, enzymes, which are involved in the biosynthesis of flavins, are possible targets for anti-infectives. Only a few flavin analogs or inhibitors of flavin biosynthesis have been subjected to detailed studies to evaluate their biological activity. Nevertheless, flavin analogs certainly have the potential to serve as basic structures for the development of novel anti-infectives and it is possible that, in the future, the urgent need for new molecules to fight multiresistant microorganisms will be met.

Inactivation of neutrophil NADPH oxidase upon dilution and its prevention by cross-link and fusion of phox proteins

Activation of the phagocyte NADPH oxidase involves assembly of p47 phox, p67 phox, Rac, and flavocytochrome b 558, and the activation can be triggered in a cell-free system with an anionic amphiphile. We find that the activated oxidase in a pure cell-free system was rapidly inactivated upon dilution. When the activated oxidase was treated with a chemical cross-linker, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, the half-life of the oxidase in dilution was extended from 1 min to 4 h at 25 °C. The cross-linked oxidase was resistant to inhibition by inactive flavin analogs, indicating that cross-linking prevents flavin exchange. When a fusion protein p67N–p47N plus RacQ61L was added, flavocytochrome b 558 became spontaneously active. Cross-linking of this mixture produced an oxidase that was extremely stable to dilution ( t 1/2 = 6.6 h). Western blotting analysis showed the presence of a cross-link between p67N–p47N and RacQ61L. These results suggest that covalently linked phox components prevents FAD loss and stabilizes the longevity of the stoichiometric complex, extending the lifespan of the active oxidase.

Catalytic mechanism of type 2 isopentenyl diphosphate:dimethylallyl diphosphate isomerase: verification of a redox role of the flavin cofactor in a reaction with no net redox change

Type 2 isopentenyl diphosphate:dimethylallyl diphosphate isomerase requires redox co-enzymes, i.e., flavin mononucleotide (FMN) and NAD(P)H, for activity, although it catalyzes a non-redox reaction. Spectrometric studies and enzyme assays under anaerobic conditions indicate that FMN is reduced through the reaction and is sufficient for activity. The sole function of NAD(P)H appears to be the reduction of FMN since it could be replaced by an alternate reducing agent. When the enzyme was reconstructed with a flavin analogue, no activity was detected, suggesting that the isomerase reaction proceeds via a radical transfer mechanism.