Design and synthesis of novel conformationally restricted peptide secondary structure mimetics

[structure: see text] A facile synthesis of the novel conformationally restricted reverse turn mimetic is described. The key features are the preparation of the alpha-keto amide and tandem bicyclic ring formation.     

Design and synthesis of a new bicyclic dipeptide isostere

The synthesis of a new Gly-Pro turn mimetic and the computational study of its ability to induce beta-turn is reported.     

The synthesis of a conformationally restricted analog of the anti-migraine drug sumatriptan

The synthesis of 5-N-Methylaminosulfonylmethyl-3-(N-methylpyrrolidin-2-ylmethyl)indole (1), a conformationally restricted analog of the anti-migraine drug, sumatriptan, is described. To incorporate our novel stereogenic replacement for the aminoethyl sidechain in sumatriptan, a convergent synthesis of the 3,5-disubstituted indole (1) was employed which utilized an intramolecular Heck reaction as the cornerstone reaction.     

3,8-Diazabicyclo[3.2.1]octan-2-one peptide mimetics: synthesis of a conformationally restricted inhibitor of farnesyltransferase

A new synthesis of the 3,8-diazabicyclo[3.2.1]octan-2-one framework is described. Transannular enolate alkylation of piperazinone derivatives provides a flexible route to highly constrained bicyclic peptidomimetic synthons with substitution at the Calpha position. The chemistry was used to produce a conformationally constrained farnesyltransferase inhibitor, which aided the elucidation of enzyme-bound conformation.     

Chiral conformationally restricted arachidonic acid analogs based on a 1,3-dioxane core

Chiral building blocks derived from l-diethyl tartrate are derivatized into various chiral arachidonic acid analogs based on a dioxane core.     

Stereoselective synthesis of new conformationally restricted analogues of a potent CGRP receptor antagonist

[structures: see text] A stereocontrolled racemic synthesis of conformationally restricted analogues 2a and 2b of a potent CGRP receptor antagonist 1 by novel functionalization of 2-substituted octahydropyrido[1,2-a]pyrazin-6-ones is described. The new diastereoselective LDA-promoted alpha-nitration of intermediate lactams established the required trans-configuration in the desired products.     

Stereoselective synthesis of novel conformationally restricted β- and γ-amino acids

Novel conformationally restricted β- and γ-amino acids containing a cyclopropane ring could be stereoselectively synthesized from readily available 5-methoxyindole and pyridine by copper(I)-catalyzed cyclopropanation with methyl diazoacetate followed by subsequent oxidative cleavage of the resulting adducts.     

Development of a new family of conformationally restricted peptides as potent nucleators of beta-turns. Design, synthesis, structure, and biological evaluation of a beta-lactam peptide analogue of melanostatin

Novel enantiopure (i)-(beta-lactam)-(Gly)-(i+3) peptide models, defined by the presence of a central alpha-alkyl-alpha-amino-beta-lactam ring placed as the (i+1) residue, have been synthesized in a totally stereocontrolled way by alpha-alkylation of suitable N-[bis(trimethylsilyl)methyl]-beta-lactams. The structural properties of these beta-lactam pseudopeptides have been studied by X-ray crystallography, Molecular Dynamics simulation, and NOESY-restrained NMR simulated annealing techniques, showing a strong tendency to form stable type II or type II' beta-turns either in the solid state or in highly coordinating DMSO solutions. Tetrapeptide models containing syn- or anti-alpha,beta-dialkyl-alpha-amino-beta-lactam rings have also been synthesized and their conformations analyzed, revealing that alpha-alkyl substitution is essential for beta-turn stabilization. A beta-lactam analogue of melanostatin (PLG amide) has also been prepared, characterized as a type-II beta-turn in DMSO-d6 solution, and tested by competitive binding assay as a dopaminergic D2 modulator in rat neuron cultured cells, displaying moderate agonist activity in the micromolar concentration range. On the basis of these results, a novel peptidomimetic design concept, based on the separation of constraint and recognition elements, is proposed.     

Design and synthesis of conformationally constrained glycosylated amino acids

To probe the conformational requirements of O-linked glycoproteins for binding to various enzymes and receptors, two conformationally constrained glycosylated amino acids, 2 and 3, were designed. The analogues were found to represent two potential low energy conformations of the parent conjugate, 1, by molecular modeling. A convergent synthesis of both 2 and 3 from D-galactose and L-methionine is presented.     

Application of tandem Ugi multi-component reaction/ring closing metathesis to the synthesis of a conformationally restricted cyclic pentapeptide

A conformationally restricted cyclic pentapeptide, containing an unsaturated 9-membered lactam as a semi-rigid scaffold, was prepared in a very convergent manner, through tandem Ugi reaction/ring closing metathesis.     

Impact of a conformationally restricted receptor on the BF2 chelated azadipyrromethene fluorosensing platform

Conformational control of the receptor-fluorophore orientation of BF2 chelated azadipyrromethene sensors reveals two photophysically different modes of analyte triggered fluorescence switching both of which exhibit large off-on fluorescence intensity responses to the light input-output of the sensors in the visible red spectral region.     

Design and facile solid-phase synthesis of conformationally constrained bicyclic peptoids

Triazine-bridged bicyclic peptoids as conformationally constrained peptidomimetics are described. Bicyclic peptoids composed of 6-12 peptoid residues (m, n = 3-6) were synthesized in excellent yields using a highly efficient solid-phase synthetic route.     

Studies directed toward the synthesis of conformationally restricted neurotransmitter analogs: The addition of N-hydroxyimides to ethyl propiolate

N-Hydroxyimides were found to add readily to ethyl propiolate to yield the imidooxyacrylates in both protic and aprotic solvents. The trans isomer only was formed in aprotic solvents while both isomers were formed in protic solvents.     

Design and synthesis of a multi-detachable benzhydrylamine-resin for solid phase peptide synthesis

Peptides with C-terminal α-carboxamides were synthesized from a multi-detachable benzhydrylamine-resin containing a Boc-(4-acetoxy)benzhydryl-amine handle of unambiguous origin. The peptides bound to the new resin are stable to trifluoroacetic acid, but are cleavable by hydrogen fluoride, base and nucleophiles to give unprotected or protected peptide fragments.     

RNA architecture dictates the conformations of a bound peptide.

BACKGROUND: The biological function of several viral and bacteriophage proteins, and their arginine-rich subdomains, involves RNA-mediated interactions. It has been shown recently that bound peptides adopt either beta-hairpin or alpha-helical conformations in viral and phage peptide-RNA complexes. We have compared the structures of the arginine-rich peptide domain of HIV-1 Rev bound to two RNA aptamers to determine whether RNA architecture can dictate the conformations of a bound peptide. RESULTS: The core-binding segment of the HIV-1 Rev peptide class II RNA aptamer complex spans the two-base bulge and hairpin loop of the bound RNA and the carboxy-terminal segment of the bound peptide. The bound peptide is anchored in place by backbone and sidechain intermolecular hydrogen bonding and van der Waals stacking interactions. One of the bulge bases participates in U*(A*U) base triple formation, whereas the other is looped out and flaps over the bound peptide in the complex. The seven-residue hairpin loop is closed by a sheared G*A mismatch pair with several pyrimidines looped out of the hairpin fold. CONCLUSIONS: Our structural studies establish that RNA architecture dictates whether the same HIV-1 Rev peptide folds into an extended or alpha-helical conformation on complex formation. Arginine-rich peptides can therefore adapt distinct secondary folds to complement the tertiary folds of their RNA targets. This contrasts with protein-RNA complexes in which elements of RNA secondary structure adapt to fit within the tertiary folds of their protein targets.     

Design and synthesis of bioactive 1,2-annulated adamantane derivatives

Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin. Oxazolone 20 showed significant trypanocidal activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being approximately 3 times more potent than rimantadine and almost 50-fold more active than amantadine.     

Solid-phase synthesis of conformationally constrained peptidomimetics based on a 3,6-disubstituted-1,4-diazepan-2,5-dione core

Starting from a Cl-trytyl linked hydroxylamine, a hydroxamic dipeptide having serine in the second position was prepared by using DMTMM as the coupling agent. Mitsunobu cyclization carried out under microwave heating gave very good yields of a 3,6-disubstituted-perhydro-diazepin-2,5-dione. This heterocycle can be used as a new platform for combinatorial chemistry or as a constraint to rigidify a small peptide.     

Target synthesis of bioactive thioglycolurils,based on QSAR predictions

Target synthesis of substituted thioglycolurils possessing sedative activity predicted by preliminary 3D-QSAR simulation of bioactive structures has been carried out.     

Studies on intramolecular Diels-Alder reactions of furo[3,4-c]pyridines in the synthesis of conformationally restricted analogues of nicotine and anabasine

En route to conformationally restricted analogues of nicotine and anabasine, a novel synthetic route to bridged anabasines is described that hinges on a domino intramolecular [4 + 2]-cycloaddition/ring opening-elimination sequence of 3-amino-substituted furo[3,4-c]pyridines. Extension of this route to bridged nicotines, however, proved abortive, even when the dienophile tether is activated by a p-tolylsulfonyl group or when the diene moiety is activated by an electron-releasing methoxy substituent. A detailed density functional theoretical study (B3LYP/6-31+G) was undertaken to provide insight into the factors that facilitate an intramolecular Diels-Alder reaction in the former case.