A step-economical multicomponent synthesis of 3D-shaped aza-diketopiperazines and their drug-like chemical space analysis.

A rapid and atom economical multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(i)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, an analysis of their 3D molecular descriptors and "drug-likeness" properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential for medicinal chemistry.

Lithium Hexamethyldisilazane Transformation of Transiently Protected 4-Aza/Benzimidazole Nitriles to Amidines and their Dimethyl Sulfoxide Mediated Imidazole Ring Formation.

Trimethylsilyl-transient protection successfully allowed the use of lithium hexamethyldisilazane to prepare benzimidazole (BI) and 4-azabenzimidazole (azaBI) amidines from nitriles in 58-88% yields. This strategy offers a much better choice to prepare BI/azaBI amidines than the lengthy, low-yielding Pinner reaction. Synthesis of aza/benzimidazole rings from aromatic diamines and aldehydes was affected in dimethyl sulfoxide in 10-15 min, while known procedures require long time and purification. These methods are important for the BI/azaBI-based drug industry and for developing specific DNA binders for expanded therapeutic applications.

Molecular Rearrangement of an Aza-Scorpiand Macrocycle Induced by pH: A Computational Study.

Rearrangements and their control are a hot topic in supramolecular chemistry due to the possibilities that these phenomena open in the design of synthetic receptors and molecular machines. Macrocycle aza-scorpiands constitute an interesting system that can reorganize their spatial structure depending on pH variations or the presence of metal cations. In this study, the relative stabilities of these conformations were predicted computationally by semi-empirical and density functional theory approximations, and the reorganization from closed to open conformations was simulated by using the Monte Carlo multiple minimum method.

Synthesis and assessment of a maleimide functionalized BF2 azadipyrromethene near-infrared fluorochrome.

The first water soluble maleimide bearing NIR BF2-azadipyrromethene (NIR-AZA) fluorochrome has been synthesised which is capable of rapid thiol conjugations in water with peptides such as glutathione, the cell penetrating peptide (CPP) C(ß-A)SKKKKTKV-NH2 and a thiol substituted cRGD. NIR fluorescence imaging showed rapid cellular delivery of the CPP conjugate and effective in vivo tumour localization for the cRGD conjugate.

A straightforward strategy toward large BN-embedded π-systems: synthesis, structure, and optoelectronic properties of extended BN heterosuperbenzenes.

A straightforward strategy has been used to construct large BN-embedded π-systems simply from azaacenes. BN heterosuperbenzene derivatives, the largest BN heteroaromatics to date, have been synthesized in three steps. The molecules exhibit curved π-surfaces, showing two different conformations which are self-organized into a sandwich structure and further packed into a π-stacking column. The assembled microribbons exhibit good charge transport properties and photoconductivity, representing an important step toward the optoelectronic applications of BN-embedded aromatics.

Cobalt- and iron-catalyzed redox condensation of o-substituted nitrobenzenes with alkylamines: a step- and redox-economical synthesis of diazaheterocycles.

A wide variety of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines. The cascade including benzylamine oxidation, nitro reduction, condensation, and aromatization occurs without any added reducing or oxidizing agent. The method can be extended to other alkylamines as reducing components or 2-nitrobenzamides as oxidizing components when using an iron/sulfur catalyst to afford various diazaheterocycles.

The facile assembly of bis-, tris- and poly(triazaphosphole) systems using "click" chemistry.

Uncatalysed 1,3-dipolar cycloaddition reactions between two phosphaalkynes, P≡CR (R = Bu(t) or Me), and a series of di-, tri- and poly-azido precursor compounds have given very high yields of a range of triazaphosphole substituted systems. These comprise the 1,1'-bis(triazaphosphole)ferrocenes, [Fe{C5H4(N3PCR)}2], the tris(triazaphosphole)cyclohexane, cis-1,3,5-C6H9(N3PCBu(t))3, and the poly(allyltriazaphosphole)s, {C3H5(N3PCR)}∞. Electrochemical studies on the 1,1'-bis(triazaphosphole)ferrocenes reveal the compounds to undergo reversible 1-electron oxidation processes, at significantly more positive potentials than ferrocene itself. Attempts to chemically oxidise one 1,1'-bis(triazaphosphole)ferrocene with a silver salt, Ag[Al{OC(CF3)3}4] were not successful, and led to the formation of a silver coordination complex, [{Fe[µ-C5H4(N3PCBu(t))]2(µ-Ag)}2][Al{OC(CF3)3}4]2, thereby demonstrating the potential the reported triazaphosphole substituted systems possess as novel ligands in coordination chemistry.

An assessment of the effectiveness of 5-methylthioninhydrin within dual action reagents for latent fingerprint development on paper substrates.

A critical investigation of 5-methylthioninhydrin (5MTN) is presented as a 'dual action' formulation component for the development of latent finger marks on paper substrates. Preparation of a dual action reagent was performed by combining proportions of 5MTN and zinc chloride (ZnCl(2)) in a pre-mixed solution. Developed prints (deposited on filter paper substrates) could be subsequently visualised in both colour and fluorescence modes. Finger mark quality was graded using a quartered print approach for a number of reagent compositions to deliver an optimised formulation recipe. To fully appraise 5MTN in comparison to currently employed chemistries, this reagent was evaluated against three alternative amino acid selective reagents, ninhydrin, 1,8-diazafluorenone (DFO) and 1,2-indandione/ZnCl(2). Six common paper types were used for this purpose and split depletion finger marks from six donors were collected. Finger mark sets were also left for two days or two weeks to show the effect of ageing on development quality. For the first time, it was shown that 5MTN/ZnCl(2) is effective as a 'dual action' reagent under the United Kingdom climate conditions. However, results presented herein show that the existing recommended chemistries and the 1,2 indandione/ZnCl(2) process are all more effective than this new latent finger mark enhancement reagent. In a preliminary sequencing study, we show the effectiveness of the existing DFO-ninhydrin sequence over dual action reagents.

Conformational analysis of trimeric maleimide substituted 1,5,9-triazacyclododecane HIV fusion scaffolds.

An analysis of the conformational preferences of three trimeric maleimide substituted 1,5,9-triazacyclododecane derivatives, proposed as cross linking reagents for HIV-1 fusion inhibitors, is presented. Exhaustive sampling was performed using the mixed Low Mode Monte Carlo conformational searching technique on the corresponding OPLS2005/GBSA(water) potential energy surface. Geometric structure, molecular length, and hydrogen bonding patterns of the compounds are analyzed. Global minimum energy structures were verified as minima using B3LYP/6-31G * geometry optimization. All structures adopt a crown-like 12-membered ring conformation; however, the system with the shortest maleimide arms (1a) can also adopt alternative ring orientations. Overall, derivatives with longer maleimide arms were more flexible and resulted in ensembles with a larger number of low energy structures. Comparison with biological inhibition data indicates that there is very little relationship between molecular size and the ability of the scaffold to orient CD4M9 miniproteins for optimal inhibition; however hydrophobicity may play a role.

Diazatetraester 1H-pyrazole crowns as fluorescent chemosensors for AMPH, METH, MDMA (ecstasy), and dopamine.

The synthesis and steady-state fluorescence studies on the interaction with AMPH, METH, MDMA, and DA of two diazatetraester pyrazole crowns containing appended N-(9H-fluoren-9-yl) and N-(naphth-2-ylmethyl) functions, in a water/ethanol 70:30 mixture at physiological pH, are described.

Stereocontrolled synthesis of trisubstituted cyclopropanes: expedient, atom-economical, asymmetric syntheses of (+)-Bicifadine and DOV21947.

[reaction: see text] An expedient, atom-economical, asymmetric synthesis of 1-aryl-3-azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.

Impact of azaproline on amide cis-trans isomerism: conformational analyses and NMR studies of model peptides including TRH analogues.

The beta-turn is a well-studied motif in both proteins and peptides. Four residues, making almost a complete 180 degree-turn in the direction of the peptide chain, define the beta-turn. Several types of the beta-turn are defined according to Phi and Psi torsional angles of the backbone for residues i + 1 and i + 2. One special type of beta-turn, the type VI-turn, usually contains a proline with a cis-amide bond at residue i + 2. In an aza-amino acid, the alpha-carbon of the amino acid is changed to nitrogen. Peptides containing azaproline (azPro) have been shown to prefer the type VI beta-turn both in crystals and in organic solvents by NMR studies. MC/MD simulations using the GB/SA solvation model for water explored the conformational preferences of azPro-containing peptides in aqueous systems. An increase in the conformational preference for the cis-amide conformer of azPro was clearly seen, but the increased stability was relatively minor with respect to the trans-conformer as compared to previous suggestions. To test the validity of the calculations in view of the experimental data from crystal structures and NMR in organic solvents, [azPro(3)]-TRH and [Phe(2), azPro(3)]-TRH were synthesized, and their conformational preferences were determined by NMR in polar solvents as well as the impact of the azPro substitution on their biological activities.