A new analytical method for anchoring quantification of amines on resin support

A rapid and quantitative method for monitoring the efficiency of coupling of amino compounds to polystyrene resin through a carbamate linker has been developed. para-Nitrophenyl carbonate activating group has been shown to release a valuable chromophore for quantitatively monitoring the progress and the yield of the reaction.     

Regiospecific synthesis of mono-N-substituted indolopyrrolocarbazoles

[reactions: see text] Two complementary and efficient strategies have been developed for the regiospecific synthesis of unsymmetrical indolopyrrolocarbazoles (IPCs) mono-N-substituted with a pentacycle. A halogen in position 2 of the intermediate bisindolylmaleimides 3a-e allows a selective Mitsunobu coupling by exploiting the increased acidity of the 2-chloro-substituted indole nitrogen. It also promotes an easier cyclization of bisindolylmaleimides 4a-e and 7b-e to IPCs. Alkylation of the 2-unsubstituted indole-3-carboxamides 2a,b and further processing to the corresponding IPCs gives access to the opposite regioisomers.     

Copper(II) in organic synthesis. IV Reaction of the copper(II) acetate complex of isatin-3-arylhydrazones with dimethyl acety-lenedicarboxylate.

The copper(II) acetate complex of isatin-3-phenylhy-drazone (2a) reacted with dimethyl acetylenedicarboxylate (DMAD) by two competitive pathways: a Cu⁺⁺ oxidation of the ligand and a [2+2] cycloaddition. The former reaction gave 3-car- benindolin-2-one (13) which reacted with DMAD in a l,3-dipolar cycloaddition, to give 3a. This was synthesized by an independent route. The phenyl radical, generated in the same process, was trapped by three DMAD and gave $\text{4a}$. The [2+2] cycloaddition gave a spiro adduct 10 which, by electrocyclic ring opening and intramolecular cyclization, allowed isolation of a pyridazino [3,4-b] indole (|5a). The reaction was performed on $\text{p}$-chlorophe-nylhydrazone 1b and the structure of 5b was demonstrated by X-ray analysis. A rationalization of the reactivity was attempted in terms of MO interactions of the reactants.     

Stereoselective synthesis of conformationally constrained cyclohexanediols: a set of molecular scaffolds for the synthesis of glycomimetics

The practical, stereoselective synthesis of the three diastereoisomeric 1,2-trans-dicarboxy-4,5-cyclohexanediols 1-3 (DCCHDs) is described, starting from a common precursor, easily available in both enantiomeric forms. The regioselective derivatization of all functional groups of 1 is also reported. The three DCCHDs are locked in a single chair conformation and thus can be used to mimic vicinally disubstituted monosaccharides of any relative configuration.     

Dansyl and dabsyl analytical constructs as tools for the accurate estimation of compounds in solid-phase synthesis

The presence of dansyl or dabsyl chromogenic moieties in a solid-phase analytical construct, an assembly of linkers/spacers/sensitizers for improving analytical characterization, allows the accurate estimation of products from solid-phase synthesis by UV detection during liquid chromatography-mass spectrometry analysis in the cleavage solution. The spectroscopic properties of dansylated molecules have been evaluated to verify the "compound-independent UV absorption" necessary for using the chromophore in the accurate estimation. First, measurements on commercial dansylated compounds were made, then a series of construct-like molecules were prepared by solution-phase synthetic procedures and their UV properties were determined. Compound calibration curves were determined, and UV absorption was shown to be both proportional to the compound concentration and compound-independent. An example of a dansyl construct derivative was then prepared on a polymeric matrix, and an accurate estimation using the calibration curves was carried out in the cleavage solution. Good agreement was found between the calculated amount of released compound using the UV calibration curves and the calculated amount using both (1)H NMR and LC/chemiluminescent nitrogen detection quantitative techniques. Preliminary studies using the dabsyl moiety as an improved chromophore with higher wavelength and extinction coefficient are also reported.     

A combinatorial approach to [1,5]benzothiazepine derivates as potential antibacterial agents

[1,5]Benzothiazepines are widely used in a number of different therapeutic areas and therefore represent an interesting scaffold for de novo exploration. Recent literature reports suggest their value as antibacterial agents. The present paper reports the exploration of this scaffold for the generation of combinatorial libraries both in solution and on solid phase.     

Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> thymidine monophosphate kinase

Abstract  

Thymidine monophosphate kinase (TMPK_mt) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2′,3′-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2′,3′-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPK_mt binding site. The three-dimensional structure of the TMPK_mt complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPK_mt target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties.     

Allylic Functionalization of 2,5- and 2,4-Cyclo-Hexadiene-1,3-Dicarboxylates

A series of 2,4- and 2,5-cyclohexadiene-1,3-dicarboxylates were functionalized at the allylic position via oxidation (SeO₂, PDC/t-BuOOH) and halogenation (NBS). The regiochemical outcome for different substrates and reactions was studied and the importance of factors such as reaction mechanism, steric hindrance and reaction intermediates stability was discussed.

     

A NMR and computational study of Smac mimics targeting both the BIR2 and BIR3 domains in XIAP protein

In this paper we report an extensive NMR analysis of small ligands (Smac mimics) complexed with different constructs of XIAP. The mimics-binding site of XIAP is known as the BIR3 domain - primary, and the linker BIR2 region - secondary site. Interactions between the BIR3 domain and Smac mimics have been extensively studied by X-ray but, as of today, there are scarce data about the interaction between BIR2, or the whole linker-BIR2-BIR3 construct, and Smac mimics. In order to characterize our Smac mimics, we performed a STD NMR study between our 4-substituted, 1-aza-2-oxobicyclo[5.3.0]decane scaffold-based molecules and three different XIAP fragments: single BIR2 and BIR3 domains, and bifunctional linker-BIR2-BIR3. The results were integrated with docking calculations and molecular dynamics simulations. NMR data, which are consistent with biological tests, indicated that the two BIR subunits interact differently with our Smac mimics and suggest that the ligands enter into more intimate contact with the linker-BIR2-BIR3. In conclusion, we observe that the SMAC mimics showed with the construct linker-BIR2-BIR3 a series of NOE contacts that were not observed in the mono-domain ligand:BIR2 or :BIR3 complexes. So, in agreement with the computational models we believe that the linker moieties of the binding site play a key role in the stability of the protein complex.