Synthesis and Structure-Activity Relationship Studies of Pyrido [1,2-e]Purine-2,4(1H,3H)-Dione Derivatives Targeting Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis.

In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named Flavin-Dependent Thymidylate Synthase (FDTS) encoded by the thyX gene was discovered; FDTS is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown pyrido[1,2-e]purine-2,4(1H,3H)-dione analogues. Several synthetics efforts were done to optimize regioselective N1-alkylation through organopalladium cross-coupling. Modelling of potential hits were performed to generate a model of interaction into the active pocket of FDTS to understand and guide further synthetic modification. All those compounds were evaluated on an in-house in vitro NADPH oxidase assays screening as well as against Mycobacterium tuberculosis ThyX. The highest inhibition was obtained for compound 23a with 84.3% at 200 µM without significant cytotoxicity (CC50 > 100 µM) on PBM cells.

Tunable Approach to C-Linked Analogs of Glycosamines.

The synthesis of (1R)-2-amino-2-deoxy-ß-l-gulopyranosyl benzene and the α and ß forms of 2-amino-2-deoxy-l-idopyranosyl benzene derivatives was accomplished through stereospecific addition of tributylstannyllithium to readily available (SR)- or (SS)-N-tert-butanesulfinyl-arabinofuranosylamine building blocks, followed by stereoretentive Pd-catalyzed Migita-Kosugi-Stille cross-coupling, stereoselective reduction, and an activation-cyclization strategy. Application of this methodology paves the way to new three-dimensional chemical space and preparation of unknown (non-natural) and complex 2-amino-2-deoxy sugars of biological interest.

A practical approach to Dideoxy-1,4- and 1,5-iminopentitols from protected sugar hemiacetals.

The convenient and straightforward preparation of dideoxy-1,4- and 1,5-iminopentitol derivatives from protected sugar hemiacetals by way of N-tert-butanesulfinyl glycosylamines and open-chain aminoalditols is reported. The synthetic procedure is a method of choice for the making of these important scaffolds of biological interest.

Glycoside Mimics from Glycosylamines: Recent Progress.

Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases and glycosyltransferases, as well as for their use as pharmacological chaperones. As they provide ready access to these important glycoside mimics, we have reviewed the most significant glycosylamine-based methodologies developed to date, with a special emphasis on the literature reported after 2006. The groups of substrates covered include N-alkyl- and N-benzyl-glycosylamines, N-glycosylhydroxylamines, N-(alkoxycarbonyl)-, and N-tert-butanesulfinyl-glycosylamines.

1-C-phosphonomethyl- and 1-C-difluorophosphonomethyl-1,4-imino-l-arabinitols as Galf transferase inhibitors: A comparison.

The convenient preparation of iminopentitol derivatives, based on a 1,4-dideoxy-1,4-imino-l-arabinitol scaffold carrying ß-phosphono(difluoromethyl) or ß-phosphonomethyl appendages, as Galf-1P mimics, is reported. The compounds were tested for their ability to inhibit GlfT2, a vital galactofuranosyltransferase involved in the cell wall biosynthesis of mycobacteria. Interestingly, the Galf-1P mimics lacking a fluorine atom (7 and 8) were very poor inhibitors, showing less than 20% inhibition of GlfT2, whereas compounds 2 and 3, which contains a difluoromethylenephosphonate moiety were more potent inhibitors. Compound 3 that is fully deprotected was the most potent showing a significant IC50 value (0.9 mm), despite the absence of the diphosphate linkage present in the parent sugar nucleotide. This study paves the way to the synthesis of more complex ß-phosphonomethyl-imino-l-arabinitol derivatives as simplified mimics of UDP-α-d-Galf.

Total synthesis of pipecolic acid and 1-C-alkyl 1,5-iminopentitol derivatives by way of stereoselective aldol reactions from (S)-isoserinal.

A short synthesis of iminosugars and pipecolic acid derivatives has been realized through aldol addition of a pyruvate, a range of ketones and (S)-isoserinal, followed by catalytic reductive intramolecular amination. The stereoselective aldol reaction was achieved successfully by using tertiary amines or di-zinc aldol catalysts, thus constituting two parallel routes to optically pure products with good yields and high diastereoselectivities. These carbohydrate analogues may be the inhibitors of potent glycosidases and glycosyltransferases.

Tunable Approach for the Stereoselective Synthesis of 1-C-Diethylphosphono(difluoromethyl) Iminosugars as Glycosyl Phosphate Mimics.

An efficient methodology for the stereoselective and tunable addition of LiCF2P(O)(OEt)2 and BrMgCF2P(O)(OEt)2 reagents to N-t-butanesulfinyl glycosylamines is described with details on the stereochemical effects at play in this process. It provides a practical route to various 1-C-diethylphosphono(difluoromethyl) iminosugars as glycosyl phosphate and sugar nucleotide mimics.

Effects of the Selected Iminosugar Derivatives on Pseudomonas aeruginosa Biofilm Formation.

A lack of an effective way to eliminate pathogenic bacteria hidden in the biofilm is a major problem in the treatment of chronic bacterial infections. Iminosugar derivatives are potential candidates for inhibitors of enzymes taking part in the biosynthesis of exopolysaccharides, which are forming bacterial biofilm. Investigated iminosugars were studied either at an early stage of biofilm formation or later on when the mature biofilm of Pseudomonas aeruginosa was already formed. A series of diverse iminosugar structures significantly inhibited biofilm formation, whereas they showed no influence on already formed biofilm. This indicates a possible mechanism of their action based on inhibition of exopolysaccharide backbone synthesis in the early stages of biofilm formation. Moreover, iminosugar derivatives did not show significant effect on the viable bacterial numbers in both early and mature biofilm forms. Importantly, they were not cytotoxic against human Caco-2 cells in vitro, which may be to their advantage in case of their medical application in preventing P. aeruginosa biofilm formation.

Chiral selectivity in the binding of [4]helicene derivatives to double-stranded DNA.

The interaction of a series of chiral cationic [4]helicene derivatives, which differ by their substituents, with double-stranded DNA has been investigated by using a combination of spectroscopic techniques, including time-resolved fluorescence, fluorescence anisotropy, and linear dichroism. Addition of DNA to helicene solutions results to a hypochromic shift of the visible absorption bands, an increase of fluorescence quantum yield and lifetime, a slowing down of fluorescence anisotropy decay, and a linear dichroism in flow-oriented DNA, which unambiguously points to the binding of these dyes to DNA. Both helicene monomers and dimeric aggregates, which form at higher concentration, bind to DNA, the former most probably upon intercalation and the latter upon groove binding. The binding constant depends substantially on the dye substituents and is, in all cases, larger with the M than the P enantiomer, by factors ranging from 1.2 to 2.3, depending on the dye.

Asymmetric Rh(II)-catalyzed cyclopropanation of alkenes with diacceptor diazo compounds: p-methoxyphenyl ketone as a general stereoselectivity controlling group.

Different diacceptor diazo compounds bearing an α-PMP-ketone group were found to be effective carbene precursors for the highly stereoselective Rh(2)(S-TCPTTL)(4)-catalyzed cyclopropanation of alkenes (EWG = NO(2), CN, CO(2)Me). The resulting products were readily transformed into a variety of biologically relevant enantiopure molecules, such as cyclopropane α- and ß-amino acid derivatives. Different mechanistic studies carried out led to a rationale for the high diastereo- and enantioselectivity obtained, where the PMP-ketone moiety was found to play a critical role in the stereoinduction process. Additionally, the use of catalytic amounts of achiral Lewis bases to influence the enantioinduction of the reactions developed is documented.

Mounting freestanding molecular functions onto surfaces: the platform approach.

A modular system has been developed to mount molecules upright onto metal surfaces in a well controlled geometry. The approach is based on a reactive platform (triazatriangulenium salt) with an electrophilic center. Functional molecules are attached via C-C bond formation. The distance from the surface can be varied by a spacer, and the distance of the functional units from each other by the size of the platform. Self-assembly of the parent triazaangulenium salt as well as the functionalized platforms on Au(111) surfaces results in stable, hexagonally ordered adlayers.

Synthesis, resolution, and VCD analysis of an enantiopure diazaoxatricornan derivative.

Using simple organic synthetic transformations, a novel diazaoxatricornan derivative, the 12 c-methyl-12-phenyl-8-propyl-12,12 c-dihydro-8 H-4-oxa-8,12-diazadibenzo[ cd, mn]pyrene ( 6a), was prepared. This novel chiral cup-shaped molecule was isolated in racemic form and in excellent yield after the addition of methyl lithium to the BF 4 salt of a novel unsymmetrical diazaoxatriangulenium cation. Compound 6a was found to be stable under classical laboratory conditions-something not obvious considering the extreme stability of the carbenium ion precursor, the electron-rich nature of the core, and the strain induced by the pyramidalization of the central carbon. The enantiomers were readily separated by chiral stationary phase chromatography, and the absolute configuration of (-)-( S)- 6a was determined by a comparison of the experimental and theoretical vibrational circular dichroism (VCD) spectra. This isolation of (-)-( S)- 6a and (+)-( R)- 6a constitutes thus the first report of a nonracemic closed-capped chiral bowl molecule for which the chirality is due to the intrinsic dissymmetry of the central core of the structure only.

Triazatriangulenium cations: Highly stable carbocations for phase-transfer catalysis.

Highly stable triazatriangulenium carbocations, of pK(R+) higher than 20, can be used as novel phase-transfer catalysts for several classical organic reactions, their intrinsic stability in strongly basic and nucleophilic conditions rendering this novel use feasible.