Synthesis of a small library of non-symmetric cyclic sulfamide HIV-1 protease inhibitors

A set of 11 non-symmetric cyclic sulfamide HIV-1 protease inhibitors were synthesized and evaluated. The use of a key microwave-assisted silver(I) oxide mediated selective mono N-benzylation reaction enabled fast and straightforward synthesis. The K_i values of the new inhibitors ranged between 0.28 μM and >20 μM.     

Altered sequence specificity identified from a library of DNA-binding small molecules

BACKGROUND: The ability to target specific DNA sequences using small molecules has major implications for basic research and medicine. Previous studies revealed that a bis-intercalating molecule containing two 1,4,5,8-napthalenetetracarboxylic diimides separated by a lysine-tris-glycine linker binds to DNA cooperatively, in pairs, with a preference for G + C-rich sequences. Here we investigate the binding properties of a library of bis-intercalating molecules that have partially randomized peptide linkers. RESULTS: A library of bis-intercalating derivatives with varied peptide linkers was screened for sequence specificity using DNase I footprinting on a 231 base pair (bp) restriction fragment. The library mixtures produced footprints that were generally similar to the parent bis-intercalator, which bound within a 15 bp G + C-rich repeat above 125 nM. Nevertheless, subtle differences in cleavage enhancement bands followed by library deconvolution revealed a derivative with novel specificity. A lysine-tris-beta-alanine derivative was found to bind preferentially within a 19 bp palindrome, without substantial loss of affinity. CONCLUSIONS: Synthetically simple changes in the bis-intercalating compounds can produce derivatives with novel sequence specificity. The large size and symmetrical nature of the preferred binding sites suggest that cooperativity may be retained despite modified sequence specificity. Such findings, combined with structural data, could be used to develop versatile DNA ligands of modest molecular weight that target relatively long DNA sequences in a selective manner.     

cis-Apa: a practical linker for the microwave-assisted preparation of cyclic pseudopeptides via RCM cyclative cleavage

A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.     

Amplification of a cyclic mixed-metalloporphyrin tetramer from a dynamic combinatorial library through orthogonal metal coordination

A cyclic porphyrin tetramer, consisting of two bis-phosphine substituted zinc(II) porphyrin units and two Rh(III)TPP units, is selected and amplified virtually quantitatively from a dynamic combinatorial library using 4,4'-bipy as a scaffold and using orthogonal binding modes.     

Phosphatase reactivity of a dicopper(ii) complex of a patellamide derivative - possible biological functions of cyclic pseudopeptides

A possible biological function of cyclic pseudo-octapeptides is presented. The dinuclear copper(ii) complex of a synthetic analogue ([Cu(2)(H(2)Pat(1))(μ-OH)(OH(2))(2)]) of the naturally occurring ascidiacyclamide is known to have a hydroxo-bridged dicopper(ii) site which is able to catalytically transform CO(2) into CO(3)(2-). This complex is shown here to function as a phosphatase mimic, suggesting that the so far unknown biological function of these macrocycles within the ascidians may involve phosphoester hydrolysis.     

Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists

Structural pre-organization of the multivalent ligands is important for successful interaction with multimeric proteins. Polymer-based heterobifunctional ligands that contain pendant groups prearranged into heterodimers can be used to probe the active site and surrounding area of the receptor. Here we describe the synthesis and activities of a series of galactose conjugates on polyacrylamide and dextran. Conjugation of a second fragment resulted in nanomolar inhibitors of cholera toxin, while the galactose-only progenitors showed no detectable activity.     

Solid-phase oligosaccharide synthesis of a small library of N-glycans

Solid-phase oligosaccharide synthesis is based on a hydroxymethylbenzyl benzoate spacer linker which is connected to the Merrifield resin (1 P). Glycosylation was performed with O-glycosyl trichloroacetimidates of glucosamine, mannose, and galactose permitting chain extension (2e, 5e), branching (4b, 7b, 8b), and chain termination (3t, 6t, 9t) with the use of O-benzyl, O-benzoyl, and N-dimethylmaleoyl as permanent and O-fluorenylmethoxycarbonyl (Fmoc) and O-phenoxyacetyl (PA) as temporary protecting groups. The steps required on solid phase are i) glycosylation under TMSOTf catalysis, ii) selective cleavage of the temporary protecting groups, Fmoc with NEt3 and PA with 0.5 equivalents of NaOMe in CH2Cl2/MeOH, and iii) product cleavage from the resin with 4.0 equivalents of NaOMe in CH2Cl2/MeOH and following O-acetylation for convenient product isolation. Thus a highly successful synthesis of a small library of seventeen N-glycan structures was made possible comprising the N-glycan pentasaccharide core structure 53 and two further chain extended hexa- and heptasaccharide N-glycans with a glucosamine or a lactosamine residue, respectively, which is attached to one of the mannose residues of the core structure (56 and 59).     

Identification from a combinatorial library of a small molecule that selectively induces apoptosis in cancer cells

The selective induction of death in cancer cells is a major challenge in modern medicine. In this communication we describe the synthesis of an 88-membered combinatorial library, and the subsequent evaluation of these compounds for their ability to selectively induce apoptosis in cancerous cells. A compound was identified from the library that induces apoptosis in U-937 and HL-60 cell lines. This compound is a remarkably selective pro-apoptotic agent for these cancer cell lines, as it does not induce significant death in noncancerous white blood cells, even at concentrations as high as 1000 muM.     

Parallel synthesis of a biased library of thiazolidinones as novel sodium channel antagonists

A biased chemical library containing 91 differentially substituted thiazolidinones was prepared in an effort to improve the pharmacology of a known anticonvulsant agent V102862. The collection was prepared in a single step multi-component condensation reaction that produced good yields and very high crude purity (75%-85%). Seven compounds, identified within the library were shown to be more potent than V102862, our parent reference compound, in an electrophysiological assay measuring sodium channel antagonism. The most potent compound, 3-(2-piperidinylethyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)thiazolidinone, has a Ki of 90 nM.     

Cu(II) coordination chemistry of patellamide derivatives: possible biological functions of cyclic pseudopeptides

Two synthetic derivatives of the naturally occurring cyclic pseudooctapeptides patellamide A-F and ascidiacyclamide, that is, H(4)pat(2), H(4)pat(3), as well as their Cu(II) complexes are described. These cyclic peptide derivatives differ from the naturally occurring macrocycles by the variation of the incorporated heterocyclic donor groups and the configuration of the amino acids connecting the heterocycles. The exchange of the oxazoline and thiazole groups by dimethylimidazoles or methyloxazoles leads to more rigid macrocycles, and the changes in the configuration of the side chains leads to significant differences in the folding of the cyclic peptides. These variations allow a detailed study of the various possible structural changes on the chemistry of the Cu(II) complexes formed. The coordination of Cu(II) with these macrocyclic species was monitored by high-resolution electrospray mass spectrometry (ESI-MS), spectrophotometric (UV/Vis) and circular dichroic (CD) titrations, and electron paramagnetic resonance (EPR) spectroscopy. Density functional theory (DFT) calculations and molecular mechanics (MM) simulations have been used to model the structures of the Cu(II) complexes and provide a detailed understanding of their geometric preferences and conformational flexibility. This is related to the Cu(II) coordination chemistry and the reactivity of the dinuclear Cu(II) complexes towards CO(2) fixation. The variation observed between the natural and various synthetic peptide systems enables conclusions about structure-reactivity correlations, and our results also provide information on why nature might have chosen oxazolines and thiazoles as incorporated heterocycles.     

Design and synthesis of conformationally constrained, extended and reverse turn pseudopeptides as Grb2-SH2 domain antagonists

A series of conformationally constrained and flexible pseudopeptide derivatives of the tripeptide pYVN were prepared as potential antagonists of interactions of phosphotyrosine peptides with the Grb2-SH2 domain. The conformationally constrained compounds contained trans- and cis-cyclopropanes as replacements to enforce locally extended and reverse turn peptide conformations, respectively.     

Efficient resolution of racemic 1,1'-bi-2-naphthol with chiral selectors identified from a small library

Efficient resolution of racemic 1,1'-bi-2-naphthol, a well-studied analyte in chiral separation, was achieved using selectors developed from a small library. Separation factors (up to 7.2) obtained are significantly higher than the ones reported previously for this analyte. The library consists of 121 members and it does not contain the pi deficient 3,5-dinitrobenzoyl (Dnb) group. These highly efficient stationary phases may lead to the practical large-scale chromatographic resolution of enantiomers of 1,1'-bi-2-naphthol, which are widely used as chiral auxiliaries and ligands in asymmetric synthesis.     

Rapid synthesis and zebrafish evaluation of a phenanthridine-based small molecule library

A Heck cyclisation approach is described for the rapid synthesis of a library of natural product-like small molecules, based on the phenanthridine core. The synthesis of a range of substituted benzylamine building blocks and their incorporation into the library is reported, together with a highly selective cis-dihydroxylation protocol that enables access to the target compounds in an efficient manner. Biological evaluation of the library using zebrafish phenotyping has led to the discovery of compound 20c, a novel inhibitor of early-stage zebrafish embryo development.     

Synthesis of protected pseudopeptides from dicarboxylic amino acids by Mitsunobu condensation

Four protected pseudopeptides from Glu-, Asp- and Gly-derivatives have been prepared via Mitsunobu condensation. It was shown to be a universal and preparative method which allows the formation of different structural molecules containing reduced peptides.     

Synthesis and partial biological evaluation of a small library of differentially-linked beta-C-disaccharides

The synthesis of a small library of differentially-linked beta-C-disaccharides has been carried out through the use of a radical allylation-RCM strategy. Acids 6 were prepared by Keck allylation of a suitable carbohydrate-based radical precursor, followed by oxidative cleavage of the formed alkene. Dehydrative coupling of these acids with the known olefin alcohol 5 then gave the precursor esters 7 in excellent yield. Methylenation of the esters 7 was followed by RCM and in situ hydroboration-oxidation of the formed glycals to furnish the protected beta-C-disaccharides 10 in good overall yield. Five examples were then deprotected and screened for their efficacy as enzyme inhibitors of beta-glycosidase and against several solid-tumor cell lines for in vitro differential cytotoxicity.     

Studies of the resolution of racemic 1,1'-bi-2-naphthol with a dipeptide chiral selector identified from a small library

Several new stationary phases were prepared to study the structure-activity relationship of the chiral resolution of racemic 1,1'-bi-2-naphthol with a modified dipeptide Asn-Asn selector. The number of amino acid, the side chain protecting groups of the amino acid, and the Fmoc end-capping group all proved important for enantioselectivity. The linker also influenced enantioselectivity. Influence of the length of the linker appears to be related to the accessibility of chiral selectors. The bond through which the selector is attached to the linker proved important. Based on these results, it is postulated that hydrogen bonding interactions between one side chain amide group of one Asn and the oxygen on the backbone of another Asn with the two hydroxyl groups of the analyte play an important role in the resolution of racemic 1,1'-bi-2-naphthol with the modified dipeptide Asn-Asn selector.     

Solid-phase synthesis of 2,3-diphenylpropionic acid library as VLA-4 antagonists

2,3-Diphenylpropionic acid library for VLA-4 antagonist was synthesized on solid-phase. Comparison of the two synthetic routes via an orthogonal generation of two aromatic amino functional groups are discussed. From this work, several compounds were identified as potent VLA-4 antagonists.     

Synthesis of a quinolone library from ynones

A library of 72 quinolones was synthesized from substituted anthranilic acids, using ynone intermediates. These masked β-dicarbonyl synthons allowed cyclization under milder conditions than previously reported quinolone syntheses.