Synthesis and evaluation of chiral bicyclic proline FKBP12 ligands (original) (raw)

Synthesis, molecular modeling and biological evaluation of aza-proline and aza-pipecolic derivatives as FKBP12 ligands and their in vivo neuroprotective effects

Bioorganic & Medicinal Chemistry, 2003

Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented. #

A Practical Ex-Chiral-Pool Synthesis of β-Proline and Homo-β-Proline

Synthesis, 1998

Starting from aspartic acid an efficient synthesis of enantiomerically pure f3-proiine and homo-f3-proiine is described. The key step of the synthesis includes formation of the 1,4-biselectrophile 6, followed by rearrangement via the aziridinium intermediate 7 and ring closure to give the pyrroiidinium salt 9a which can serve as a common precursor for both target compounds.

Synthesis of Ketone Analogues of Prolyl and Pipecolyl Ester FKBP12 Ligands

Journal of Medicinal Chemistry, 2002

The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.

Design, synthesis, and biological activity of novel polycyclic aza-amide FKBP12 ligands

Journal of Medicinal Chemistry

Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.

2-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural Studies

Organic Letters, 2001

2-Aryl-2,2-difluoroacetamido-proline and pipecolate esters are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 phenyl ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.

3-Substituted Prolines: From Synthesis to Structural Applications, from Peptides to Foldamers

Molecules, 2013

Among the twenty natural proteinogenic amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing hydrogen bond formation. Despite the lack of hydrogen bonds and thanks to conformational restriction of flexibility linked to the pyrrolidine ring, proline is able to stabilize peptide secondary structures such as -turns or polyproline helices. These unique conformational properties have aroused a great interest in the development of proline analogues. Among them, proline chimeras are tools combining the proline restriction of flexibility together with the information brought by natural amino acids side chains. This review will focus on the chemical syntheses of 3-substituted proline chimeras of potential use for peptide syntheses and as potential use as tools for SAR studies of biologically active peptides and the development of secondary structure mimetics. Their influence on peptide structure will be briefly described.

Asymmetric synthesis of a new proline analogue

Journal of the Chemical Society, Chemical Communications, 1981

The 1,3-dipolar cycloaddition to ethylene of N-glycosylnitrones, formed in situ from the partially protected D-mannose-or D-ribose-oximes and various glyoxalates, gave compounds which could be transformed into both enantiomers of 3-t-butoxycarbonyl-isoxazolidine and derivatives thereof. ANALOGUES of proline possessing a heterocyclic ring other than pyrr~lidinel-~ are useful biochemical probes.* We report the asymmetric synthesis of the two enantiomers of isoxazolidine-3-carboxylic acid ('5-oxaproline') and of some of their derivatives. The synthesis is based on the 1,3dipolar cycloaddition of N-glyco~ylnitrones~ ,6 to ethylene. When the partially protected D-mannose-, or D-riboseoximes (1)6 and (2)6 were allowed to react with 1-3 to 3 mol. equiv. of the glyoxylic esterst (3), (4), or (5), in the

A straightforward route to enantiopure 2-substituted-3,4-dehydro-β-proline via ring closing metathesis

Amino Acids, 2011

The synthesis of unusual cyclic amino acids, that may be envisaged as proline analogs, is an area of great interest for their potential applications as scaffolds for the design of bioactive peptidomimetics or units for the creation of novel foldamers. We have carried out the preparation of cyclic dehydro-b-amino acids starting from allylic carbonates via a two-step allylic amination/ring closing metathesis (RCM) protocol. The introduction of the allylamino moiety has been carried out either without a catalyst, through an S N 2 0 reaction, or in the presence of iridium complexes. The backbone of the allylamino intermediates contains two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffolds. A similar reaction has been already reported in the literature for racemic aromatic-substituted substrates, but no examples of enantiopure derivatives bearing aliphatic chains have been reported. The reaction was optimized by testing different Grubbs' catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-b-amino acids as central core of peptidomimetics, the malonate chain was also used to protect nitrogen prior to RCM.

[2.2]Paracyclophane-Derived Chiral P,N-Ligands

With the idea of tuning structural flexibility and rigidity, several [2.2]paracyclophane-derived P,N-ligands were designed and synthesized. A full investigation of the relationship between the ligands' structures and their abilities to induce asymmetry in palladium-catalyzed asymmetric allylic alkylations of malonates with 1,3-diphenyl 2-propenyl acetate was carried out, and high yields and enantioselectivities (i.e., 99% yield, 97% ee) were observed while using ligands bearing matched planar and central chirality.