Synthesis and antagonist activities of 4-aryl-substituted conformationally restricted cyclopentenyl and cyclopentanyl-glutamate analogues

The conformationally restricted glutamate analogues, 4-aryl-1-amino-2-cyclopentene-1,3-dicarboxylates and their cyclopentane analogues have been prepared in a diastereoselective manner. Biological studies of 12a and 12b indicates that both compounds are modest antagonists at mGluR2.     

Spirophostins: conformationally restricted analogues of adenophostin A

The synthesis, biological evaluation, and molecular modeling of two conformationally restricted analogues of adenophostinA (1), denominated as spirophostin (3R)-10 and (3S)-11, as novel ligands for the D-myo-inositol 1,4,5-trisphosphate receptor (IP3R), is presented. These diastereoisomeric spiroketals are synthesized by spiroketalization of D-glucose derivatives (2S)-15 and (2R)-16, separation of the protected isomers (3R)-19 and (3S)-20, followed by phosphorylation and deprotection. The spirophostins (3R)-10 and (3S)-11 display comparable biological activity, with a 3H-IP3-displacing and Ca2+-releasing potency less than IP3 and adenophostin A.     

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.     

Synthesis of conformationally restricted nicotine analogues by intramolecular [3+2] cycloaddition

We describe the synthesis of a series of conformationally constrained nicotine analogues 2-5 from appropriate pyridine-containing enals, featuring an intramolecular azomethine ylide-alkene [3+2] cycloaddition. The objective of the current project is to develop new selective nAChRs-targeting ligands. Of the nicotine analogues that we have studied, the conformation-restricting ring B unit can be either a five-membered carbocycle, or a six-membered carbocycle or heterocycle. The present work constitutes a general method for rapid assembly of other related tricyclic nicotine analogues.     

Synthesis of conformationally constrained lysine analogues

The synthesis of two conformationally constrained lysine analogues is reported. The synthesis of the novel analogue 1 based on the 3-aza-bicyclo[3.1.0]hexane system is accomplished from the known tricycle 3 in eight steps. The synthesis of the analogue 2 is accomplished in eight steps from 4-hydroxy proline. Both analogues are synthesized appropriately protected for Fmoc/Boc solid-phase peptide synthesis.     

Synthesis of a conformationally restricted polyoxygenated crownophane

A new polyoxygenated crownophane has been synthesized from syringaldehyde and diethyleneglycol by means of McMurry pinacol reaction, whereas ring closing metathesis with Grubbs’ catalyst failed in producing the macrocyclization to the corresponding stilbenophane. The NMR data of the crownophane show a restricted conformational space accessible to the phenyl rings.     

Synthesis of bicyclo[3.1.0]hexane derivatives as conformationally restricted analogues of beta-arabinofuranosyl and alpha-galactofuranosyl rings

A route for the synthesis of bicyclo[3.1.0]hexane-derived conformationally restricted analogues of beta-arabinofuranosyl and alpha-galactofuranosyl rings is described. Advantage is taken of the pseudo-enantiomeric relationship between the two ring systems to develop a route that provides both targets from a single precursor. Key steps include a base-promoted ring contraction of an epoxy ketone obtained from cyclohexane-1,4-dione to give the bicyclo[3.1.0]hexane ring system and a late stage resolution involving esterification with O-acetyl-(S)-mandelic acid.     

Synthesis of febrifuginol analogues and evaluation of their biological activities

A new series of febrifuginol analogues was prepared from l-glutamic acid. An antimalarial activity evaluation against chloroquine-sensitive (T96) and chloroquine-resistant (K1) Plasmodium falciparum indicated that all the tested compounds had very strong inhibitory activity. Compounds 4 and 17b′ were inactive against KB, MCF7, HepG2 and LU1 cell lines even at a concentration of 100 μM, while they exhibited significant inhibition towards P. falciparum. Comparison of the antimalarial activity and the cytotoxic properties revealed that the 2′S isomers were more active than the corresponding 2′R isomers for this series of febrifuginol analogues, indicating that the C-2′ position is critical for the biological activity of this class of compounds.     

Lactone and cyclic ether analogues of platelet-activating factor. Synthesis and biological activities

Six-membered lactone and tetrahydropyran analogues of platelet-activating factor (PAF), 4-11, and related antagonistic derivatives 41-46 were synthesized. None of the delta-lactones 4-7 showed PAF-like activities, while the corresponding cyclic ethers 8, 9 and 11 were slightly active. Some of the cyclic antagonists showed more potent inhibitory activities than the open chain antagonist CV-3988 against platelet aggregation (rabbit platelet-rich plasma, IC50) and hypotension (rat, ID50) induced by C16-PAF: e.g. dl-3-[6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2- yl)methyl]phosphonoxy]hexylthiazolium (inner salt) (41d) (IC50 5.5 x 10(-7) M, ID50 0.046 mg/kg, i.v.); dl-3-[5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2- yl)methyl]phosphonoxy]pentylthiazolium (inner salt) (43c) (IC50 5.7 x 10(-7) M, ID50 0.076 mg/kg, i.v.).     

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.     

Synthesis of conformationally restricted acetylcholine analogues. Comparing lipase-mediated resolution with simulated moving bed chromatography of arylated β-hydroxy-pyrrolidines

The enantiodivergent synthesis of new, conformationally restricted acetylcholine analogues was accomplished using arylated endocyclic enecarbamates as key intermediates. Stereoselective hydroboration of the aryl enecarbamates provided the corresponding aryl-β-hydroxy-pyrrolidines. Acetylation, deprotection, followed by N-bismethylation, led to the desired betaine products. The kinetic resolution of the intermediate alcohols was performed by lipase-mediated hydrolysis of its acetate derivatives, resulting in excellent enantioselectivities (E > 100). An enzymatic enantiopreference predicted by the Kazlauskas’s model was confirmed following Riguera’s protocol. Finally, chromatographic resolution of racemic alcohol 5a was evaluated by semi-preparative scale chiral simulated moving bed chromatography and its performance compared with biocatalysis.     

Synthesis of conformationally restricted sulfonamides via radical cyclisation

A convenient synthesis of conformationally restricted sulfonamides such as compounds (12) and (40) with seven- and eight-membered ring structures has been achieved using radical reaction. These compounds and their analogs are expected to serve as important pharmacophores in drug discovery.     

Synthesis of conformationally restricted dinucleotides by ring-closing metathesis

[reaction:see text] The ring-closing metathesis reaction has been used in the synthesis of conformationally restricted dinucleotides as well as a 3'-nucleotide analogue. From bis-allylic nucleoside phosphates obtained from simple nucleoside precursors, the synthesis of unsaturated cyclophosphates has been accomplished using either Grubbs' catalyst or an improved analogue. Hereby, the conformational freedom of the nucleic acid phosphordiester linkage has been efficiently constrained.     

Synthesis of conformationally constrained spirodihydrofuropyridine analogues of epibatidine

Conformationally constrained spirofuropyridine analogues of epibatidine, syn-2 and anti-2, in which the 7-azabicyclo[2.2.1]heptane system and the 2-chloropyridine ring are held rigidly with the shorter and longer N-N distances, respectively, were synthesized from N-Boc-7-azabicyclo[2.2.1]heptan-2-one. The preliminary binding studies suggested that syn-2 has stronger binding affinity for nAChRs than anti-2.     

Synthesis of conformationally constrained analogues of RGD tripeptide

Convergent syntheses of N-functionalized (3S,4S)-3-amino-4-vinyl-piperidin-2-one 10, trans-3-substituted proline 18 and (3S)-3-amino-piperidin-2-one 28 are developed. By incorporating these building blocks to an appropriate position, conformationally constrained analogues of RGD tripeptide (Arg-Gly-Asp) 2, 3 and 4 are designed and synthesized.     

Synthesis of conformationally locked versions of puromycin analogues

Conformationally locked North and South versions of puromycin analogues built on a bicyclo[3.1.0]hexane pseudosugar template were synthesized. The final assembly of the products was accomplished by the Staudinger-Vilarrasa coupling of the corresponding North (2 and 3) and South (6 and 7) 3'-azidopurine carbanucleosides with the Fmoc-protected 1-hydroxybenzotriazole ester of 4-methoxy-L-tyrosine. North azides 2 and 3 were reported earlier. The 3'-azido intermediates 6 and 7 that are necessary for the synthesis of the South puromycin analogues are described herein for the first time.     

Synthesis and supramolecular properties of conformationally restricted and flexible phospholipids

Short synthetic routes are described to produce structurally related phospholipids that are either conformationally restricted or flexible. The conformationally restricted structures have a cyclopropyl ring in the interfacial region of the phospholipid. The key synthetic step is a cyclopropanation reaction between 2(5H)-furanone and a stabilized chloroallylic phosphonate anion. The synthetic routes enable the incorporation of different polar headgroups as well as nonpolar tails at late stages in the sequence. The phosphoethanolamine derivatives 1b and 2b readily form encapsulating vesicles, however, dye leakage from vesicles composed of the restricted phospholipid 1b is significantly slower than from vesicles composed of flexible analogue 2b. Physicochemical analyses using 31P NMR, differential scanning calorimetry, fluorescence anisotropy, and Langmuir-Blodgett films suggest that the decreased permeability of membranes composed of conformationally restricted 1b is due to its ability to pack more closely in a bilayer assembly.     

Synthesis and chromatographic resolution of conformationally constrained analogues of homotaurine

The first series of conformationally constrained analogues of homotaurine is reported. The partial constriction of the skeleton was realized through the insertion of a cyclopropyl ring, between the α,β- and β,γ-positions, thus affording, respectively, trans- and cis-2-aminomethylcyclopropane-1-sulfonic acids and trans- and cis-(2-aminocyclopropyl)methanesulfonic acids. The resolution of all four racemic mixtures was accomplished using HPLC system carrying the polysaccharide-based Chiralpak^® IB^® column as the chiral stationary phase. The coupling with an ‘Evaporative Light Scattering Detector (ELSD)’ has been particularly valuable during the chromatographic study.