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Air oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine which afforded 2,5,8,11-tetraaza-5,11-dihydro-4,10-dihydroxyperylene-1,3,6,7,9,12-hexaone is described. The X-ray crystallography of the product revealed that it exists in the meso form in the solid state which is slightly less stable than the enantiomeric form and that the two forms interconvert rapidly at room temperature.

Two alkyl phosphate derivatives of the 6,7-dihydro-6,7-dioxo-8-ribityllumazine system were synthesized and found to be inhibitors of Bacillus subtilis and Mycobacterium tuberculosis lumazine synthase as well as Escherichia coli riboflavin synthase. The possible binding modes of these compounds were investigated through molecular modeling of complexes.

Investigating a potential DNA-threading agent designed and synthesized on the basis of the hypothetical binding model of indenoisoquinolines in the DNA-topoisomerase I 'cleavage complex'. The presently reported alkaline autoxidative cleavage reaction of the C11 alkenyl side chain in the indenoisoqinoline 12 is a novel transformation.

Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin, a vitamin that is involved in many critical biochemical reactions that are essential for the maintenance of life. The ribitylamino N-H moiety of the lumazine synthase substrate was replaced by CH2 and N-CH3 groups in order to obtain inhibitors and structural and structural probes that could be useful in studying the structures of bound reaction intermediates.

Research has been conducted on the 7-oxo-8-ribitylaminolumazine's 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives. The synthesis of these derivatives as inhibitors of Escherichia coli riboflavin synthase and Bacillus subtilis lumazine synthase has been carried out and the details are presented.

Research has been conducted on the metabolically stable epimeric covalent hydrates A and B of 6,7-bis(trifluoromethyl)-8-D-ribityllumazine. The complex formed from epimer A and a recombinant has been investigated in confirming the stereochemical assignments based on the epimer B results and the details are reported.

Research has been conducted on the riboflavin synthase catalyzing dismutation reaction. The synthesis of the 9-D-ribityl-1,3,7-trihydropurine-2,6,8-trione has been carried out and the results indicate that this compound is a potent inhibitor of the Escherichia coli riboflavin synthase and Bacillus subtilis lumazine synthase.

Research has been conducted on the non-nucleoside reverse transcriptase inhibitors in the alkenyldiarylmethane series. The use of the Sonogashira and Stille cross-coupling reactions in the synthesis of these inhibitors is discussed.

This article documents occurrence of a new reaction product during the treatment of dithioacetal with mercuric chloride and mercuric oxide in the presence of aqueous acetone. Nuclear magnetic resonance spectral data indicate that it is an aldehyde and identified as 2,3:4,5-di-O-isopropylidene-D-ribitol.

Research has been conducted on the Bacillus subtilis lumazine synthase wild type and mutant protein interactions. The effect of (super)19 F NMR ligand shift perturbation agents on these interactions has been investigated.

The cosalane pharmacophore was extended through the attachment of two additional substituted benzoic acid rings via amide and methylene linkers. The resulting compounds showed substantial antiviral activity when tested in vitro for inhibition of the cytopathic effects of HIV-1(sub RF) in CEM-SS cells and HIV-1(sub IIIB) in MT-4 cells. The compound containing the methylene linker also indicated moderate activity against HIV-2(sub ROD) in MT-4 cells.

A study on catalytic reactions involving riboflavin synthase was conducted to investigate the participation of two identical lumazine molecules as enzyme substrates for riboflavin synthase. Results of the study suggest that the incorporation of bis(6,7-dimethyl-8-D-ribityllumazines) as potential bisubstrate analogue inhibitors of riboflavin synthase could be of interest. Experimental methodology, findings and conclusions are presented.

The synthesis of three phosphonic acid inhibitors of lumazine synthase revealed that the phosphonate 6-(6-D-ribitylamino-2,4-dihydroxypyrimidin-5-yl)-1-hexylphosphonic acid is the most potent lumazine synthase inhibitor and has a Ki of 130 microM. This compound may be useful in the design and synthesis of more potent inhibitors of lumazine synthase for therapeutic use as an antibiotic. Its molecular bonding behavior and lumazine synthase-binding activities are also discussed.

A study was conducted on the stereochemistry of the reaction of thiols with brefeldin A. The findings indicate that the Michael addition of thiols to brefeldin A is a highly distereoselective reaction. This diastereoselectivity results in ratios of major to minor diastereomers of at least 30:1. Moreover, the major diastereomers have the 3R configuration while the minor diastereomers are assigned the 3S configuration.

A method for the synthesis of lavendustin A and representative analogs was developed based on the convenient solid phase synthetic strategy. The synthetic process is a base-labile linker approach that avoids protection/deprotection steps. The sensitive para-hydroxylated phenolic target molecules were formed in good yields and superior purities by the careful optimization of the cleavage conditions of the solid phase synthetic process.

Research was conducted to examine the design and synthesis of (ribitylamino)uracils bearing fluorosulfonyl, sulfonic acid and carboxylic acid functionality as inhibitors of lumazine synthase. The experiment has provided three additional lumazine synthase inhibitors, one of which is the most potent inhibitor described to date. Results provide additional insight that may enable the future design of more potent inhibitors.

A method for the synthesis of lavendustin A and representative analogs was developed based on the convenient solid phase synthetic strategy. The synthetic process is a base-labile linker approach that avoids protection/deprotection steps. The sensitive para-hydroxylated phenolic target molecules were formed in good yields and superior purities by the careful optimization of the cleavage conditions of the solid phase synthetic process.

Aldol intermediates formed by the reaction of lithium enolates of ketones with butyl oxy carbonyl (BOC)-alpha amino aldehydes and ketones, cyclize in acidic medium to give pyrroles. The BOC-amino aldehydes and BOC-amino ketones are prepared from alpha-amino acids. This synthetic method is very versatile for the preparation of substituted and fused pyrrole systems. Moderate yield of products is obtained, which are purified from thin-layer or column chromatography on silica gel.

The mechanism and the prospects is presented for the reaction of 2'-hydroxy-5'-methoxychalcones with thallium (III) nitrate in methanol, resulting in the oxidative transformation of the chalcones to 4,5-dialkoxy aurones. In this transformation, the solvent-derived alkoxy group is attached at C-4 of the aurone. The oxidative transformation occurs without the rearrangement of either ring A or ring B of the chalcone.

A deacylation reaction, mediated by tetra-n-butylammonium fluoride, involves 1,3 O to C shift of a silyl group in an aromatic system and this could be due to an anionic species. The transformation is intramolecular and a migrating silyl group displaces an acyl group. This transformation is observed in the conversion of 2-acetyl-3,17-bis(tert-butyldimethylsilyl)-beta-estradiol and 3,17-bis(tert-butyldimethylsilyl)-2-propionyl-beta-estradiol to 2,17-bis(tert-butyldimethylsilyl)-beta-estradiol.

N-(tert-butoxycarbonyl)-O-(dimethylphosphono)-L-tyrosine was used to synthesize phosphotyrosine-containing peptides by embedding phosphotyrosine residue in a sequence surrounding Tyr 527 in c-src. Dimethyl protection was used for the phosphate of phosphotyrosine, while deprotection was employed under acid conditions during the synthesis.

A mixture of four aldol products 5a-d in a 3:3:1:1 ratio was obtained from the reaction of cyclopentanone enolate (7) with Boc-L-phenylalaninal (6). Lactone 13a and phosphate 12 were obtained by samarium iodide reduction, preceded by the reaction of 5a with diethyl phosphorocyanidate. A crystalline lactam 15a resulted from the conversion of (1R,1'S,2S, 2'S)-2-(2'-amino-1'-hydroxy-3'-phenylpropyl)cyclopentanecarboxylic acid lactone (14a), which was obtained from the deprotection of 13a. X-ray studies confirmed the structure of 15a.

A study used the reaction of 5-amino-4-((D-ribityl) amino)-2,4-(1H,3H)-pyrimidinedione hydrochloride (3. HCl) with trifluoropyruvaldehyde hydrate to prepare 6-(trifluoromethyl)-8-(D-ribityl) lumazine to examine its reactivity at C-7 and its binding to riboflavin synthase of Bacillus subtilis. Lumazine develops only a single major anionic species, where the oxygen of the 3'-hydroxyl groups on the ribityl side chain binds covalently to C-7 of the lumazine, causing the subsequent development of a pyran ring. Lumazine bound to the enzyme less tightly than the covalent adducts from lumazine.

Sulfuric acid, salicylic acid, sodium nitrite and formaldehyde were allowed to undergo a prolonged reaction to afford high molecular weight aurintricarboxylic acid polymers. The structure of the nine fractions purified from the reaction was determined using nuclear magnetic resonance spectral analysis. The activity of the fractions against HIV-1 and -2 was likewise studied. Results indicate that the anti-HIV effect of high molecular weight aurintricarboxylic acid polymers increased with size up to seven to 12 kiloDalton. Thereafter, anti-HIV effects either plateau or decrease.

The synthesis of 6-(trifluoromethyl)-7-oxo-8-(D-ribityl)lumazine and its 7-methyl analogue leadsto a study of their inhibition mechanism against the light riboflavin synthase of Bacillus subtilis. The two are obtained by reacting methyl trifluoropyruvateand 1,1,1-trifluorobutane-2,3-dione, respectively, with 5-amino-6-(D-ribitylamino)-2,4-pyrimidinedione. Equilibrium dialysis and spectroscopic studies show that the 7-oxo-lumazine binds with the enzyme at three donor and three acceptor sites while the 7-methyl analogue binds at threesites, at a ratio of one molecule per site.

Aurintricarboxylic acid (ATA), a heterogeneous mixture of polymers obtained by treatment of salicylic acid with sulfuric acid, formalin and sodium nitrite, is fractionated via thin-layer chromatography on silica gel. Nine low molecular weight fractions are isolated and characterized by a battery of NMR spectroscopic methods. In bioassays subsequently conducted, four of the fractions exhibit significant protection against HIV-1 in CEM cell cultures at near-cytotoxic levels.

Preparation of 6-(trifluoromethyl)-7-oxo-8-ribityllumazine involves an elimination of the 7-CF3 moiety from 6,7-bis(trifluoromethyl)-7-hydroxy-8-ribityllumazine. Mechanistic study suggests deprotonation of the 7-OH group as the first step. Lumazine synthase riboflavin synthase of Bacillus subtilis catalyzes the elimination reaction and the enzyme decreases the pKa of the 7-OH group to induce diastereoselectivity.

Either mono- or dibromination of benzyl methyl ethers is achieved by controlling the amount of NBS and the temperature. The elimination of methyl bromide from the monobrominated intermediates has produced aromatic aldehydes, whereas hydrolysis of the dibrominated intermediates has yielded aromatic methyl esters.

A high-throughput screening (HTS) hit compound has exhibited moderate inhibition of Mycobacterium tuberculosis and Escherichia coli riboflavin synthases. The HTS hit compound and its analogues have provided the first examples of riboflavin synthase inhibitors with antibiotic activity.

(E)-5-Nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione is identified as a novel inhibitor of Schizosaccharomyces pombe lumazine synthase by using high-throughput screening of a 100000 compound library. The optimization of the enzyme inhibitory activity through the structure modification of the lead compound (E)-5-nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione has led to (E)-5-nitro-6-(4-nitrostyryl)pyrimidine-2,4(1H,3H)-dione.

The stereoselective synthesis of a series of 3,3-diarylacrylonitriles as tubulin polymerization inhibitors for potential use in cancer chemotherapy is reported. The synthetic pathway involved stannylcupration and palladium-catalyzed Stille cross-coupling chemistry, facilitating both E and Z isomers of 3,3-diarylacrylonitriles to be prepared in a very short sequence of reactions.

Three metabolically stable analogues of the hypothetical intermediate obtained after phosphate elimination in the lumazine synthase-catalyzed reaction are synthesized and analyzed as lumazine synthase inhibitors. The crystal structure of Mycobacterium tuberculosis lumazine synthase in complex with one of the inhibitors has provided a model of the conformation of the intermediate occurring immediately after phosphate elimination.

The preparation of the structural and mechanistic probes of lumazine synthase and riboflavin synthase enzymes as well as their inhibitory potential value as antibiotics is reported. The synthesis was carried out by designing a sulfur analogue of the pyrimidine substrate of the lumazine synthase-catalyzed reaction and product of the riboflavin synthase-catalyzed reaction.

The synthesis of several potent inhibitors of the lumazine synthases of a number of important human pathogens, including Mycobacterium tuberculosis and Candida albicans is described. The key steps in the synthesis are C-5 deprotonation of 4-chloro-2,6-dimethoxypyrimidine, acylation of the resulting anion, and conversion of the product to a pyrazolopyrimidine with hydrazine.

The condensation of Schiff bases with homophthalic anhydrides provides a mixture of cis- and trans-4-carboxy-3,4-dihydro-3-phenyl-1-(2H)isoquinolones. A route for conversion of the trans diastereomers to indenol[1,2-c]isoquinolines using selenoxide elimination and Friedel-Crafts cyclization chemistry is presented.

A series of ribitylpurinetriones bearing alkyl phosphate and alpha,alpha-difluorophosphonate substituents are synthesized. The alpha,alpha-difluorophosphonate analogue is found to be an inhibitor of Mycobacterium tuberculosis lumazine synthase with K(sub i) of 60 nM.

Research has been conducted on hypothetical intermediate analogues in the reaction catalyzed by lumazine synthase. The synthesis and analysis of these analogues as inhibitors of Bacillus subtilis lumazine synthase and Escherichia coli riboflavin synthase are described.

Research was conducted to attempt the osmium-catalyzed dihydroxylation of the double bond of the allyl group in the indenoisoquinoline. The hydroxylated products were subjected to the reaction conditions to examine the possible roles of the C-12 hydroxylated indenoisoquinolines as intermediates in the transformation. Results demonstrate that the conversion of indenoisoquinolines to isoquinoline-3-spiro-3'-phthalides is unusual and cannot be rationalized easily by traditional alkene osmylation chemistry.

Camptothecins (CPTs) are the prototypical class of topoi-somerase I (Top1) inhibitors with significant anticancer activities. Structure activity relationship studies have demonstrated that inverting the stereochemistry at C-20 (R-CPT) or changing the E-ring lactone to a lactam (CPT-lactam) abolishes the Top1 inhibitory activity. The explanations that have been advanced for these effects are that there is either a failure of hydrogen bond formation involving the C-20 hydroxyl group of R-CPT or a failure of E-ring opening of the lactam, which have been proposed to be required for Top1 inhibition. We demonstrate here that the preferred conformation for the CPTs has the 20-Et pseudo-axial, while the 20-OH is pseudoequatorial, and therefore, the 20-OH groups in all the three CPT analogues (S-CPT, R-CPT, and CPT-lactam) are able to hydrogen bond with Asp533. The loss of the Top1 inhibitory activity by the latter two CPT analogues is attributed to the decreased π-π stacking interaction energy with the neighboring base pairs compared to the natural S-CPT. The differences in π-π stacking interaction energies are derived from the differential electrostatics on the E-ring. [ABSTRACT FROM AUTHOR]

Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin, an essential metabolite that is involved in electron transport processes. To obtain structural probes of these two enzymes, as well as inhibitors of potential value as antibiotics, a series of ribitylpurinetriones bearing alkyl phosphate and α,α-difluorophosphonate substituents were synthesized. Since the purinetrione ring system and the ribityl hydroxyl groups can be alkylated, the synthesis required the generation of these two moieties in protected form before the desired alkylation reaction could be carried out. These substances were designed as intermediate analogue inhibitors of lumazine synthase that would bind to its phosphate-binding site. All of the compounds were found to be effective inhibitors of both Bacillus subtilis lumazine synthase as well as Escherichia coli riboflavin synthase. Molecular modeling of the binding of 3-(1,3,7,9tetrahydro-9-D-ribityl-2,6,8-trioxopurin-7-yl)propane 1-phosphate provided a structural explanation for how these compounds are able to effectively inhibit both enzymes. Interestingly, the enzyme kinetics of these new compounds in comparison with the parent purinetrione demonstrated unexpectedly that the phosphate and phosphonate substituents contributed negatively to the binding. A possible explanation for these effects on lumazine synthase would be that the inorganic phosphate in the assay buffer competes with the substituted purinetriones for binding to the enzyme. This would be consistent with the observed increase in Km of the 3,4-dihydroxybutanone-4-phosphate substrate from 5.2 µM in Tris buffer or from 6.7 µM in MOPS buffer to 50 µM in phosphate buffer when tested on Bacillus subtilis lumazine synthase. However, when tested in Tris buffer vs Mycobacterium tuberculosis lumazine synthase, three of the phosphate inhibitors displayed inhibition constants in the 4-5 nM range, indicating that they are much more potent than the parent purinetrione. Under these conditions, the phosphate moieties of the inhibitors do contribute positively to their binding. The α,α-difiuorophosphonate analogue, which is expected to have enhanced metabolic stability relative to the phosphates, was also found to be an inhibitor of Mycobacterium tuberculosis lumazine synthase with a Ki of 60 nM. [ABSTRACT FROM AUTHOR]

Presents a study which looks at the synthesis and design of (ribitylamino) uracils which bear fluorosulfonyl, carboxylic acid and sulfonic acid functionality as inhibitors of lumazine synthase. Role of the enzyme, riboflavin synthase; Details on the mechanism proposed for the lumazine synthase-catalyzed reaction; Details on experiments.

Employs protected amino acid during the synthesis of PheThrSerThrGluProGlnTyr(PO3Me2)GlnProGlyGluAsnLeu during which problems involving incomplete incorporation of the Thyr(PO3Me2) residue and partial demethylation of the dimethylphosphono group and dephosphorylation during peptide synthesis were encountered. Encounter of an acid catalyzed backbone rearrangement.