Design of novel conformationally restricted analogues of glutamic acid

Stereomeric 3-carboxy-Δ²-isoxazoline-cyclopentane amino acids, which represent restricted conformations of glutamic acid, have been prepared through a strategy based on the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to a suitably protected 1-amino-cyclopent-2-enecarboxylic acid. These amino acids, assayed at iGluRs and mGluRs, proved to be inactive. The biological data have been accounted for through the comparison of their conformational profile with that of a 3-carboxy-Δ²-isoxazolinyl proline (CIP-A) and (±)-1-aminocyclopentane-1,3-dicarboxylic acid.     

Pyrrolidine PNA: a novel conformationally restricted PNA analogue

[reaction:see text] A new conformationally restricted PNA adenine monomer has been synthesized in 13 steps from cis-4-hydroxy-D-proline. A fully modified adenine decamer displayed improved binding affinity toward complementary DNA and RNA oligonucleotides as compared to that of the parent PNA adenine decamer.     

Synthesis of pyrrolidinone PNA: a novel conformationally restricted PNA analogue

To preorganize PNA for duplex formation, a new cyclic pyrrolidinone PNA analogue has been designed. In this analogue the aminoethylglycine backbone and the methylenecarbonyl linker are connected, introducing two chiral centers compared to PNA. The four stereoisomers of the adenine analogue were synthesized, and the hybridization properties of PNA decamers containing one analogue were measured against complementary DNA, RNA, and PNA strands. The (3S,5R) isomer was shown to have the highest affinity toward RNA, and to recognize RNA and PNA better than DNA. The (3S,5R) isomer was used to prepare a fully modified decamer which bound to rU10 with only a small decrease in Tm (delta Tm/mod = 1 degree C) relative to aminoethylglycine PNA.     

1-amino-2-phenylcyclopentane-1-carboxylic acid: a conformationally restricted phenylalanine analogue

DFT calculations at the B3LYP/6-311G(d,p) level have been used to investigate the intrinsic conformational preferences of 1-amino-2-phenylcyclopentane-1-carboxylic acid (c5Phe), a constrained analogue of phenylalanine in which the alpha and beta carbons are included in a cyclopentane ring. Specifically, the N-acetyl-N'-methylamide derivatives of the cis and trans stereoisomers, where cis and trans refer to the relative position between the amino group and the phenyl ring, have been calculated. Solvent effects have been examined using a self-consistent reaction field (SCRF) method. Results indicate that the conformational space of the cis stereoisomer is much more restricted than that of the trans derivative both in the gas phase and in solution.     

A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones

Conformationally restricted analogues of β-methylaspartic acid were easily prepared starting from chiral N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group lying at C-3 of the pyrrolidin-2-one ring.     

Chemistry of vinyl sulfones. Approach to novel conformationally restricted analogues of glutamic acid

A totally different approach to conformationally restricted glutamic acid analogues is described, in which one of the acid functions is replaced by a cyclopropanol. The reactivity of cyclopropanol vinyl sulfones toward addition of lithiated Schöllkopf bislactim ether provides a facile synthesis of α-amino acid diastereoisomers. Conformational analysis of these analogues, incorporating solvation effects, and docking to a glutamate receptor model, are used to show the relevance of the conformational restrictions employed.     

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.     

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.     

Preferred 3D-structure of peptides rich in a severely conformationally restricted cyclopropane analogue of phenylalanine

Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.     

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.     

Efficient microwave-assisted synthesis of 4-amino-2-benzazepin-3-ones as conformationally restricted dipeptide mimetics

In this paper, we describe the synthesis of conformationally constrained dipeptide mimetic derivatives. Microwave flash heating was used in several synthetic steps providing the opportunity to perform the reactions in dramatically shortened time as well as to increase the obtained yields. The efficiency of the methodology makes it useful in order to prepare other dipeptides containing the 4-amino-tetrahydro-2-benzazepin-3-one motif.     

Synthesis of P,N-heterocycles from omega-amino-H-phosphinates: conformationally restricted alpha-amino acid analogs

P,N-heterocycles (3-hydroxy-1,3-azaphospholane and 3-hydroxy-1,3-azaphosphorinane-3-oxide) are synthesized in moderate yield from readily available omega-amino-H-phosphinates and aldehydes or ketones via an intramolecular Kabachnik-Fields reaction. The products are conformationally restricted phosphinic analogs of alpha-amino acids. The multigram-scale syntheses of the H2N(CH2)(n)PO2H2 phosphinic precursors (n = 1, 2, 3) and some derivatives are also described.     

Non-steroidal antiinflammatory agents. VI. Synthesis of 10-oxo-5H-pyrrolo[1,2-b]isoquinoline-3-acetic Acid,a conformationally restricted analogue of tolmetin

The synthesis of 10-oxo-5H-pyrrolo[1,2-b]isoquinoline-3-acetic acid 4 , a tricyclic analogue of tolmetin which might show significant analgesic-antiinflammatory activity, has been accomplished in four steps. Alkylation of ethyl 2-pyrrolylglyoxylate ( 15 ) with 2-cyanobenzyl bromide afforded derivative 16 , which was transformed by the Huang-Minion reaction into the dicarboxylic acid 6 . Cyclization of this key intermediate to 17 , followed by alkaline hydrolysis, afforded 10-oxo-5H-pyrrolo[1,2–6]isoquinoline-3-acetic acid ( 4 ). Various attempted syntheses of 6 are also discussed.     

Naphthalimide-thiazoles as novel photonucleases: molecular design, synthesis, and evaluation

A new family of photonucleases, naphthalimide-thiazoles was synthesized and evaluated. These compounds intercalated into DNA efficiently and damaged DNA photochemically at concentrations as low as 5 μM. Mechanistic experiment suggests that a novel naphthalimide-thiazole radical produced via an excited triple state might be involved in the DNA photodamage. Different activity may arise from the impact of substituents at 2-phenyl ring of thiazole on the electron population of excited triple state according to AM1 semi-empirical calculation.     

Synthesis of (3S,5S)-3,5-diaminopiperidin-2-one as a conformationally restricted surrogate of Dab-Gly dipeptide

An efficient and stereospecific synthesis of chiral 3,5-diaminopiperidin-2-one as a novel conformationally restricted surrogate of 2,4-diaminobutanoyl (Dab)-Gly dipeptide has been achieved. The key steps include (i) ruthenium tetroxide (RuO₄) oxidation of N-Boc-2-azidomethylpyrrolidines with a catalytic amount of RuO₂·xH₂O in a two-phase system of aq NaIO₄/AcOEt and (ii) intramolecular transamidation of the resulting 2-azidomethylpyrrolidin-2-ones with 10% Pd–C in MeOH/H₂O (12/1, v/v) under an H₂ atmosphere (3 atm). This methodology represents a powerful tool for the synthesis of Dab-Gly dipeptide surrogate.     

Synthesis of an analogue of lavendamycin and of conformationally restricted derivatives by cyclization via a hemiaminal intermediate

Quinoline 12 was obtained by a Friedländer reaction from 2-aminobenzaldehyde and methyl acetoacetate. Reduction, silylation then oxidation provided compound 8a. A Pictet-Spengler reaction between the latter and tryptophan methyl ester yielded compound 14, then compound 7 by desilylation. Numerous attempts to prepare a cyclized derivative of this analogue of lavendamycin 7 by conventional ways failed. Fortunately, a good result was obtained via a hemiaminal intermediate and compound 21 was thus obtained in satisfactory yield. A conjugate addition occurred in the course of its reduction which led to compound 22. Biological tests were carried out with compound 7 and the conformationally restricted analogues 21 and 22.     

Design of a conformationally restricted analogue of the antiepilepsy drug Vigabatrin that directs its mechanism of inactivation of gamma-aminobutyric acid aminotransferase

The antiepilepsy drug vigabatrin (1, 4-aminohex-5-enoic acid, gamma-vinylGABA) is known to be a mechanism-based inactivator of the pyridoxal phosphate (PLP)-dependent enzyme gamma-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M.; Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9341-9349). The major pathway involves gamma-proton removal, tautomerization into the PLP ring, followed by Michael addition of an active site lysine residue at the conjugated vinyl group to give a stable covalent adduct with the protein (Scheme 2, pathway a). The minor inactivation mechanism also involves gamma-proton removal, but tautomerization occurs through the vinyl group, followed by an enamine rearrangement that leads to attachment of the inactivator to the PLP, which is bound to the protein (Scheme 2, pathway b). The cause for the two different inactivation pathways was hypothesized to be potential overlap of the incipient carbanion with the pi-orbitals of both the PLP and the vinyl group. With use of the crystal structure data for GABA-AT recently reported (Storici, P.; Capitani, C.; De Biase, D.; Moser, M.; John, R. A.; Jansonius, J. N.; Schirmer, T. Biochemistry 1999, 38, 8628-8634) a computer model of vigabatrin bound to the PLP was constructed and energy minimized. This model indicated that the major Michael addition pathway could only occur if the vinyl group were allowed to rotate by 180 degrees. A conformationally rigid analogue of vigabatrin, cis-3-aminocyclohex-4-ene-1-carboxylic acid (9), was designed to prevent bond rotation and block the Michael addition pathway. A detailed study of the mechanism of inactivation of GABA-AT by 9 revealed that it inactivates by a single mechanism, the enamine pathway.