Acyclic Analogues Research Articles

NATURAL BOND ORBITAL ANALYSIS OF CYCLIC AND ACYCLIC “C-H” ACIDS

The high acidity of Meldrum’s acid, barbituric and tetronic acids in comparison to their acyclic analogues was explained by density functional theory and calculations and by natural bond orbital analysis. The present study shows that cyclic b-dicarbonyl compounds are remarkably stabilized by intramolecular donor-acceptor interactions and this effect is absent in their acyclic analogues.

Extraction of triaquatrinitrorhodium form with calix[n]arenethiaethers from nitric acid nitrite–nitrate solutions

Comparison of extraction properties of macrocyclic calix[4,6]arenethiaethers (CATE) with their acyclic analogs R2S (R = C6H13, C8H17) for the recovery of [Rh(NO2)3(H2O)3]0 rhodium form from nitric acid solutions was carried out. Rhodium recovery with CATE (0.05 M) in the absence of accelerating additives under optimal conditions exceeds 90% at 5–10-fold preconcentration and is only 1–3% for R2S (1 M). Extraction kinetics was studied and hypothesis on the mechanism of multiple acceleration of rhodium recovery was proposed for CATE extraction, the mechanism includes the formation of intermediate product of colloidal- chemical nature on account of the surface activity of the macrocycle and its reaction with rhodium accompanied by rhodium chelation to the sulfur atoms of neighboring fragments of the macrocycle. The obtained results are of interest for the development of methods for the isolation of fission rhodium from nitrate–nitrite nitric acid solutions.

Synthesis and Kinetic Analysis of Two Conformationally Restricted Peptide Substrates of Escherichia coli Penicillin-Binding Protein 5.

Escherichia coli PBP5 (penicillin-binding protein 5) is a dd-carboxypeptidase involved in bacterial cell wall maturation. Beyond the C-terminal d-alanyl-d-alanine moiety, PBP5, like the essential high-molecular mass PBPs, has little specificity for other elements of peptidoglycan structure, at least as elicited in vitro by small peptidoglycan fragments. On the basis of the crystal structure of a stem pentapeptide derivative noncovalently bound to E. coli PBP6 (Protein Data Bank entry 3ITB ), closely similar in structure to PBP5, we have modeled a pentapeptide structure at the active site of PBP5. Because the two termini of the pentapeptide are directed into solution in the PBP6 crystal structure, we then modeled a 19-membered cyclic peptide analogue by cross-linking the terminal amines by succinylation. An analogous smaller, 17-membered cyclic peptide, in which the l-lysine of the original was replaced by l-diaminobutyric acid, could also be modeled into the active site. We anticipated that, just as the reactivity of stem peptide fragments of peptidoglycan with PBPs in vivo may be entropically enhanced by immobilization in the polymer, so too would that of our cyclic peptides with respect to their acyclic analogues in vitro. This paper describes the synthesis of the peptides described above that were required to examine this hypothesis and presents an analysis of their structures and reaction kinetics with PBP5.

Synthesis of Acyclic Nucleoside Analogues through the Insertion of Carbenoids into N−H Bond of Nucleobases

AbstractA new and efficient approach for the synthesis of acyclic nucleoside analogues with different side chains has been established for the first time via the insertion of carbenoids into N−H bond of nucleobases. With Sc(OTf)3 as the catalyst, various purine bases and α‐diazoesters worked well, and gave the corresponding acyclic nucleosides in moderate‐to‐good yields (21 examples, up to 87 % yield) with good N9‐regioselectivities (up to >99:1). Moreover, other N‐heterocycles including pyrimidines, benzoimidazole, imidazole, carbazole, and pyrazole are also suitable substrates and afford the desired N−H insertion products with moderate‐to‐good yields. In addition, the enantioselective and chiral auxiliary induction N−H insertion reactions were also studied.

Binding mode prediction of aplysiatoxin, a potent agonist of protein kinase C, through molecular simulation and structure–activity study on simplified analogs of the receptor-recognition domain

Aplysiatoxin (ATX) is a naturally occurring tumor promoter isolated from a sea hare and cyanobacteria. ATX binds to, and activates, protein kinase C (PKC) isozymes and shows anti-proliferative activity against human cancer cell lines. Recently, ATX has attracted attention as a lead compound for the development of novel anticancer drugs. In order to predict the binding mode between ATX and protein kinase Cδ (PKCδ) C1B domain, we carried out molecular docking simulation, atomistic molecular dynamics simulation in phospholipid membrane environment, and structure–activity study on a simple acyclic analog of ATX. These studies provided the binding model where the carbonyl group at position 27, the hydroxyl group at position 30, and the phenolic hydroxyl group at position 20 of ATX were involved in intermolecular hydrogen bonding with the PKCδ C1B domain, which would be useful for the rational design of ATX derivatives as anticancer lead compounds.

Novel and Efficient Synthesis of gem‐Difluorinated Derivatives of Acyclic Nucleoside Phosphonates (ANPs)

AbstractA novel efficient method for the synthesis of gem‐difluorinated derivatives of acyclic nucleotide analogues has been developed. The method is based on utilization of diethyl difluoromethylphosphonate as a nucleophilic difluoromethylation reagent. In contrast to previous difluoromethylation procedures using commercially available DAST or deoxofluor, this process is very robust, proceeds under mild conditions and is accompanied only by small amounts of by‐products. The reaction of diethyl difluoromethylphosphonate with 2‐benzyloxyacetaldehyde afforded 3‐(benzyloxy)‐1,1‐difluoropropan‐2‐ol (6) a key precursor for syntheses of difluoromethylated analogues of various acyclic nucleoside phosphonates.

Interference with purinergic signalling: an explanation for the cardiovascular effect of abacavir?

The association of abacavir (ABC), a guanosine analogue, with cardiovascular toxicity is a long-lasting matter of controversy engendered by the lack of a mechanism of action. Clinical data point to an acute mechanism of vascular inflammation. Previous studies have shown that ABC induces leukocyte-endothelial cell interactions, an indicator of vascular inflammation. These effects are reproduced by another purine analogue, didanosine, but not by pyrimidine or acyclic nucleotide analogues, hinting at an interference with the purinergic system. The aim of the present study was to assess the role of ATP-receptors in leukocyte accumulation induced by ABC. Clinical concentrations of ABC were analysed in an animal model in vivo (intravital microscopy using male C57BL/6 wild-type or P2rx7 knockout mice), in human endothelial cells and leukocytes in vitro (flow chamber), or in leukocyte Mac-1 expression (flow cytometry). ABC reduced leukocyte rolling velocity and increased rolling flux and adhesion both in vivo and in vitro. These effects were absent in P2rx7 knockout mice and following the specific blockade of ATP-P2X7 receptors in wild-type animals. Further pharmacological characterization in flow chamber experiments confirmed the role of ATP-P2X7 receptors and suggested that those located on leukocytes were particularly implicated. Activation of ATP-P2X7 receptors is needed for expression of leukocytic Mac-1. Similar effects were obtained with didanosine. ABC induces leukocyte-endothelial cell interactions through a mechanism involving interference with purine-signalling pathways via ATP-P2X7 receptors located mainly on leukocytes. Our data are compatible with existing clinical data revealing an increased cardiovascular risk in ABC-treated patients.

ChemInform Abstract: A Chemoenzymatic Route to Prepare Acyclic Nucleoside Analogues

Abstractinvolving an aldol condensation of aldehydes of various nucleobases catalyzed by a dihydroxyacetone phosphate‐dependent aldolase (rabbit muscle aldolase)

Synthesis and characterization of new acyclic nucleosides analogues derived from 2-phenyl quinoline candidates

Reaction of 4-substituted quinoline hydrazide with some aldohexoses and aldopentoses gave a series of new N-β-glycosides. The following cyclization of N-β-glycosides with acetic anhydride led to O-acetyl-[5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-yl]-D-glycosides. Structure of the newly synthesized products was elucidated by chemical and spectroscopic methods.

Ferrocene-containing macrocyclic triazoles for the electrochemical sensing of dihydrogen phosphate anion

Two novel ferrocene-containing macrocyclic triazoles (L1 and L2) and their acyclic analogs (L3 and L4) were easily prepared by “click” reaction. The anions binding abilities of L1–L4 were evaluated by cyclic voltammetry and differential pulse voltammetry methods. The results revealed that the receptors L1–L4 have exclusive electrochemical sensing of H2PO4−, with the shift in redox potentials of L1–L4 towards the cathodic values. The binding mechanisms between the receptors and H2PO4− were examined by 1H NMR titrations and density functional theory (DFT) calculations.

Cooperative Reactivity in an Extended-Viologen-Based Cyclophane.

A tetracationic pyridinium-based cyclophane with a box-like geometry, incorporating two juxtaposed alkyne functions, has been synthesized. The triple bonds are reactive through cycloadditions toward dienes and azides, promoted by the electron-withdrawing nature of the pyridinium rings, as well as by the strain inherent in the cyclophane. The cycloadditions proceeded in high yields, with the cyclophane reacting faster than its acyclic analogue. While the cyclophane contains two reactive triple bonds, there is no evidence for a stable monofunctional intermediate-only starting material and the difunctional product have been detected by (1)H NMR spectroscopy. Molecular modeling of the energy landscape reveals a lower barrier for the kinetically favored second cycloaddition compared with the first one. This situation results in tandem cascading reactions within rigid cyclophanes, where reactions at a first triple bond induce increased reactivity at a distal second alkyne.

A Chemoenzymatic Route To Prepare Acyclic Nucleoside Analogues

AbstractAcyclic nucleosides are potential antiviral and antitumor agents. In this work, their preparation through a novel chemoenzymatic procedure involving the N‐alkylation of a nucleobase and subsequent aldol condensation catalyzed by a dihydroxyacetone phosphate‐dependant aldolase (Rabbit Muscle Aldolase, RAMA) is described.

Discovery of novel quinazolinones and their acyclic analogues as multi-kinase inhibitors: design, synthesis, SAR analysis and biological evaluation

MCF-7 IC50 = 0.000012 μM; MDA-MB-231 IC50 = 0.00010 μM; HS-578T IC50 = 0.00045 μM, ABL IC50 = 0.011 nM.

Synthesis and Antimicrobial Activity of New Synthesized Benzimidazole Derivatives and their Acyclic Nucleoside Analogues

New benzimidazole derivatives and their N-substituted acyclic nucleoside analogues were prepared. The synthesized compounds were tested for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, Micrococcus, Salmonella typhi and Salmonella para typhi. The synthesized compounds were tested also against fungi species such as Aspergillus flavus, Aspergillus fumigates, Aspergillus ochraceus and Candida albicans. Most of tested compounds exhibited moderate to high antimicrobial activity while few compounds were found to exhibit little or no activity against the tested microorganisms.

Synthesis and Antimicrobial Activity of New Synthesized Benzimidazole Derivatives and their Acyclic Nucleoside Analogues

A chalcone was prepared by the reaction of 1,4-diacetylbenzene with benzaldehyde. Reaction of this chalcone with cynanothioacetamide/guanidine hydrochloride and malnonitrile in presence of piperdene afforded the corresponding pyridine, pyrimidine, and pyrans derivatives in good yields respectively. Further, bis-chalcone 1 was cyclized to pyrazole analogs by using thiosemicarbazide, semicarbazide and tertiarybutylcarbazate. The newly heterocyclic compounds have been characterized by IR, 1H-NMR and elemental analyses.

Aminophobanes: hydrolytic stability, tautomerism and application in Cr-catalysed ethene oligomerisation

9-Amino-9-phosphabicyclo[3.3.1]nonanes, (PhobPNHR'; R = Me or (i)Pr) are readily prepared by aminolysis of PhobPCl and are significantly less susceptible to hydrolysis than the acyclic analogues Cy2PNHR'. Treatment of Cy2PNHMe with Cy2PCl readily gave Cy2PNMePCy2. By contrast, treatment of PhobPCl with PhobPNHMe in the presence of Et3N does not afford PhobPNMePPhob but instead the salt [PhobP(= NMeH)PPhob]Cl is formed which, upon addition of [PtCl2(NC(t)Bu)2] gives the zwitterionic complex [PtCl3(PhobP(= NMeH)PPhob)]. The neutral PhobP(= NMe)PPhob is accessible from PhobNMeLi and is converted to the chelate [PdCl2(PhobPNMePPhob)] by addition of [PdCl2(cod)]. The anomalous preference of the PhobP group for the formation of PPN products is discussed. The unsymmetrical diphos ligands PhobPNMePAr2 (Ar = Ph, o-Tol) are prepared, converted to [Cr(CO)4(PhobPNMePAr2)] and shown to form Cr-catalysts for ethene oligomerisation, producing a pattern of higher alkenes that corresponds to a Schulz-Flory distribution overlaid on selective tri/tetramerisation.

DFT study of the hydrolysis reaction in atranes and ocanes: the influence of transannular bonding.

Thermochemical kinetics of hydrolysis reactions of compounds with transannular intramolecular M…N bonds, i.e., atranes RM(OCH2CH2)3N and ocanes R2M(OCH2CH2)2NH (M = Si, Ge; R = F, Cl, Me), is studied at the B3LYP/aug-cc-pVDZ theoretical level. Several DFT methods are assessed for the reproduction of the experimental activation barrier for the Si-O bond cleavage of 1-methylsilatrane. Activation barriers for atranes and ocanes show the tendency for their growth with the decrease of the electronegativity of a substituent R on going from F to Me and their decrease from Si to Ge. Hydrolysis activation barriers of atranes and ocanes are compared with those of their acyclic analogs RM(OCH3)3 and R2M(OCH2)2NH in order to study the role of transannular M…N bonds in the stability of these molecules to hydrolysis. Substantially larger barriers for atranes support the opinion that stability of atranes may be explained by the formation of intramolecular bonds; however, the strengthening of transannular M…N bonds results in lower M-O cleavage barriers. It was proposed that the M-O cleavage barrier height is determined not by a weak M…N bonding itself, but rather by the contribution of a nitrogen lone pair to the antibonding orbitals of M-O bonds. The NBO analysis show that this interaction increases with the decrease of the electronegativity of a substituent R and decreases on going from atranes to ocanes. In ocanes, the presence of M…N bonds does not kinetically hinder the hydrolytic process; M-O cleavage activation barriers for acyclic analogs are higher. M-Hal cleavage barriers are substantially higher than those for M-O cleavage for R = F, but lower for R = Cl. Graphical Abstract The experimental barrier height of the Si-O bond cleavage in 1-methylsilatrane is well reproduced when three explicit water molecules are included in the B3LYP/aug-cc-pVDZ theoretical model.

Phosphonylated 8-Azahypoxantines as Acyclic Nucleotide Analogs

GRAPHICAL ABSTRACT

Quantification of the Nucleophilic Reactivities of Cyclic β‐Keto Ester Anions

AbstractKinetics of the reactions of enolate anions derived from acyclic and cyclic β‐keto esters with benzhydrylium ions and quinone methides have been determined photometrically in dimethyl sulfoxide solution at 20 °C. The reactions follow second‐order rate laws: first‐order with respect to the electrophile and first‐order with respect to the enolate. Reactions conducted in the presence of 18‐crown‐6 ether and in the presence of variable concentrations of K+ allowed the influence of ion‐pairing on the nucleophilic reactivities of the various enolate ions to be determined quantitatively. Enolate ions derived from oxocycloalkanecarboxylic esters show reactivities similar to those of their acyclic analogue. Enolate ions derived from δ‐lactones are less nucleophilic, which is explained by the enforced (E) conformation of the corresponding esters.

Toward a Molecular Lego Approach for the Diversity-Oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems.

A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through α-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent iminosugars.