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The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize N-(purin-6-yl)dipeptides containing the terminal fragment of (S)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of N-(purin-6-yl)-(S)-amino acids to dimethyl (S)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of N-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (S,S)- and (R,S)-diastereomers (6:4). Individual (S,S)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of N-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of N-(purin-6-yl)-(S)-alanine as N-(9-benzylpurin-6-yl)-(S)-alanine and N-(7-deazapurin-6-yl)-(S)-alanine. It was found that coupling of these compounds to dimethyl (S)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory Mycobacterium tuberculosis H37Rv strain (MIC 3.1–6.25 μg/mL) were identified. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, AT part of Springer Nature.

N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.Copyright © 2020 Elsevier Masson SAS

N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.Copyright © 2020 Elsevier Masson SAS

S-adenosyl-l-methionine (AdoMet), an important biological cofactor, exists in two chiral forms, (S,S)- and (R,S)-, only the former of which is biologically active. Here, we have developed a chromatographic method to obtain pure (S,S)-AdoMet using a single C18 column.

S-adenosyl-l-methionine (AdoMet), an important biological cofactor, exists in two chiral forms, (S,S)- and (R,S)-, only the former of which is biologically active. Here, we have developed a chromatographic method to obtain pure (S,S)-AdoMet using a single C18 column.

1,3-Dienyl-2-silanols with a wide range of substitution patterns are readily obtained by palladium-catalyzed silaboration of 1,3-enynes followed by Suzuki-Miyaura cross coupling with aryl bromides. Subsequent Hiyama-Denmark cross coupling with aryl iodides provides either 1,3- or 1,2-dienes in high yields. The site selectivity can be fully controlled by the choice of activator used in the coupling reaction. In the presence of strong bases such as NaOt-Bu, KOt-Bu, and NaH, clean formation of 1,2-dienes takes place via allylic rearrangement. In contrast, stereo- and site-selective formation of tetra- and trisubstituted 1,3-dienes results from use of Ag 2O and Bu 4NF·3H 2O, respectively, as activators. Under microwave heating at 100 °C the base-mediated cross couplings are largely accelerated and are completed within one hour or less. The ratio of diastereomeric allenes varies depending on the substitution pattern of the silanol and ranges from >99:1 to 52:48., QC 20121120

English: Pentoxifylline [1-(5'-oxohexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione], sold under the trade name Trental®, is a methylxanthine derivative used in treatment of peripheral and cerebrovascular diseases and poor regional microcirculation (intermittent claudication). It has recently been investigated as an antitumor agent. It improves tumor perfusion and influences cytokine –mediated inflammation. Our objectives were to synthesise 1-(3-oxobutyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione and some of its derivatives for use as internal standards in the determination of biological fluids by liquid chromatography and for pharmaceutical/ biological screening as enzyme inhibitors. These efforts were hampered by the low reactivity of the N-1 position on the theobromine towards alkylation with electrophiles. As an alternative method to achieve the aforementioned goals, we investigated the photochemistry of pentoxifylline. Of particular interest was the fact that pentoxyphylline has two chromophores, i.e. carbonyl and xanthine, separated by a linear butyl alkyl chain. We now report a series of photochemical reactions of pentoxifylline and reaction conditions that were used to synthesise novel analogues. The carbonyl moiety reacted predictably to yield three products in toluene. Norrish II fission yielded 1-allyl-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (A) in yields of up to 40%, and Yang cyclisation yielded (R*, R*,)-(±)-1-{[2-Hydroxy-2-methylcyclobutyl]methyl}-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione/(B) (10% yield). The ratio of these two products was always 4:1. The expected racemic 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione / lisophylline (C) (6.5% yield) was isolated via photo-reduction of the carbonyl group to an alcohol. From TLC chromatograpy it appeared that tributyltin hydride increased the yield of these three products. A subsequent HPLC analysis proved this to be wrong, but affirmed the 4:1 ratio of A: B, Afrikaans: Pentoksifelien (1-(5’-oksoheksiel)-3,7-dimetielxantien), word as Trental® bemark. Dit is ’n metielxantien derivaat wat gebruik word vir priferale en cerebrovaskulere siektes en swak mikrosirkulasie. Dit word ook ondersoek as ’n potensiële antikankermiddel. Dit verbeter tumor perfusie en het ’n effek op sitokien gekoppelde inflammasie. Ons het probeer om pentoksifelien en derivate daarvan te maak vir gebruik as interne standaarde vir die kwantifisering daarvan in ligaamsvloeistowwe met vloeistofchromatografie en om dit te toets vir biologiese aktiwiteit as ensieminhibeerders. Ons pogings het misluk weens die lae reaktiwiteit van die N-1 posisie van xantien teen alkilering met elektrofiele. Ons het gevolglik fotochemiese metodes ondersoek om derivate van pentoksifelien te maak. Dit is nog nooit vantevore gedoen nie. Ons het veral belang gestel in die feit dat pentoksifelien twee chromofore het (karboniel en xantien gedeelte) wat deur ’n lineêre –(CH2)4- alkielketting geskei word. Ons rapporteer nou ’n reeks fotochemiese reaksies van pentoxifelien en die gepaardgaande reaksietoestande wat ons gebruik het om nuwe derivate te maak. Die karbonielgedeelte reageer soos verwag om drie produkte te lewer. Norrish II splyting lewer 1-alliel-3,7-dimetielxantien in opbrengste van tot 50%. Yang siklisering lewer 1-[(2-hidroksie-2-metelsiklobutiel)metiel]-3,7-dimetielxantien (12.5% opbrengs). Die verhouding tussen hierdie twee produkte was altyd 4:1. Ons isoleer ook die verwagte lisofelien (10% opbrengs) weens die reduksie van die karbonielgroep na ’n alkohol. Volgens dunlaagchromatografie het dit gelyk of byvoeging van tributieltinhidried tot verhoogde opbrengste gelei het. Hoëdrukvloeistofchromatografie het egter getoon dat dit nie die geval was nie en ook die 4:1 verhouding onder verskillende reaksietoestande bevestig. In benseen is geen lisofelien verkry nie. Dit dui aan dat tolueen as waterstofdonor optree in die fotochemiese reduksie van die karbonielgroep. Tributi, FARMOVS-PAREXEL, The Technology and Human Resources for Industry Programme

An asymmetric Lewis acid-mediated [2,3]-sigmatropic rearrangement of allylic amines has been developed, affording the corresponding homoallylic amines in good yield and excellent enantioselectivities. The rearrangement proceeds by complexation of the chiral Lewis acid to the amine followed by deprotonation and rearrangement., QC 20100831

Herein is described the synthesis of surfactants featuring polyhydroxylated head groups. Three head groups were prepared via consecutive stereoselective dihydroxylations of a diene. By coupling of these with lipophilic tail groups six novel surfactants have been prepared. The monolayers prepared from four of these have been investigated at the air-water interface. Significant differences were observed between monolayers consisting of enantiomerically pure surfactants contra racemates as well as between diastereomers., QC 20100930

Using 1H NMR two diastereoisomers of the ethacrynic acid glutathione conjugate (EASG) as well as ethacrynic acid (EA) could be distinguished and quantified individually. Chemically prepared EASG consists of equal amounts of both diastereoisomers. GSTP1-1 stereospecifically catalyzes formation of one of the diastereoisomers (A). The GSTP1-1 mutant C47S and GSTA1-1 preferentially form the same diastereoisomer of EASG as GSTP1-1. Glutathione conjugation of EA by GSTA1-2 and GSTA2-2 is not stereoselective. When human melanoma cells, expressing GSTP1-1, were exposed to ethacrynic acid, diastereoisomer A was the principal conjugate formed, indicating that even at physiological pH the enzyme catalyzed reaction dominates over the chemical conjugation. Copyright (C) 1998 Federation of European Biochemical Societies.

A cascade approach has been developed towards dual C-C bond formation via consecutive C-H functionalization/cyclization giving access to pyrrolo[1,2-a]indoles in a highly regio- and diastereoselective manner using catalytic [Ru(p-cymene)Cl2]2. The methodology was further expanded to attain pentacyclic structures involving manifold C-C bond creation. © 2017 The Royal Society of Chemistry.

A high-yielding, temperature switchable divergent approach towards the synthesis of either spiro-indolenines or quinolines is described, starting from easily available indolyl ynones. The application of TFA at rt promotes the dearomatization of the indole, resulting in the formation of the spiro-indolenine, while at higher temperature, rearrangement results in the formation of the quinoline. © The Royal Society of Chemistry 2017.