Christophe Dugave

Practical synthesis of Boc and Fmoc protected 4-fluoro and 4-difluoroprolines from trans-4-hydroxyproline

Abstract Boc- cis -4-fluoro-L-proline and 4-difluoro-L-proline, usable in classical peptide synthesis, were obtained in respectively 71% (3 steps) and 65% (4 steps) overall yields from the readily available trans -4-hydroxy-L-proline methyl ester. The corresponding fluorinated trans -isomer was isolated in 24% yield (5 steps). Transformation of Boc-protected compounds to their Fmoc-equivalents was performed in high yields.

Synthesis of natural and non natural orthogonally protected lanthionines from N-tritylserine and allo-threonine derivatives

Abstract The reactivity of electrophiles derived from N -tritylserine, threonine and allo -threonine esters toward a selection of nucleophiles was investigated. Best yields from substitution products were obtained with N -trityliodoalanine and soft nucleophiles such as thiols. This strategy was applied to the synthesis of lanthionines, the monosulfide analogs of cystine. Orthogonally protected sulfide adducts from L- and D-cysteines, threo - β -methyl-L-cysteine and D-penicillamine were isolated in 81–88% yield (ee>98%). This strategy was applied to the prepration of lanthionine and cyclolanthionine suitably protected for peptide synthesis.

Synthesis of optically pure N-Boc-protected (2R,3R)- and (2R,3S)-3-fluoroprolines

Abstract Non-protein amino acids (2 R ,3 R )- and (2 R ,3 S )-3-fluoroprolines were synthesized as novel probes for studying the cis / trans isomerization of the amino acylproline peptide bond. The N -Boc-protected target compounds were obtained as optically pure material starting from (2 S ,3 S )-3-hydroxyproline.

Combinatorial Self‐Assembly of Cyclophilin hCyp‐18 Ligands through Rhenium Coordination

Combinatorial self-assembly of organic molecules through metal coordination is an attractive method of generating molecular diversity for the selection of catalysts, sensors and receptors, supramolecular architectures, including synthetic proteins, and protein ligands. We describe herein an application of this strategy for synthesizing potentially bioactive small molecules for in vitro and in vivo studies. This strategy is based on the association of two independent modules A and B through the complementary complexation of a metal core M. Connection of modules A and B gives stable metal complexes A·M·B, which can then be screened for their ability to bind a target protein (Scheme 1). Conversely, molecules A and B alone are not anticipated to display significant biological ACHTUNGTRENNUNGactivity.

Interaction of human cyclophilin hCyp-18 with short peptides suggests the existence of two functionally independent subsites

The binding of peptides, derived from the model substrate Suc‐Ala‐Ala‐Pro‐Phe‐pNA, to the human cyclophilin hCyp‐18 was investigated. HCyp‐18 is able to bind 2–4‐mer peptides as well as shorter para‐nitroaniline (pNA) derivatives and pNA surrogates. Although Suc‐Ala‐Phe‐pNA binds hCyp‐18, only proline‐containing peptides are able to block efficiently the peptidyl‐prolyl cis/trans isomerase activity. Competition experiments strongly suggest the existence of two independent subsites: a S1′ ‘proline’ subsite and a S2′–S3′ ‘pNA’ subsite. The interaction at S2’–S3’ requires either a Phe‐pNA C‐terminus or a Phe‐pNA surrogate bearing an H‐bond acceptor able to bind Trp121 and Arg148 simultaneously.

Dynamic combinatorial self-assembly of cyclophilin hCyp-18 ligands through oxorhenium coordination.

The dynamic combinatorial assembly of independent modules A and B through oxorhenium(V) coordination by a NS2+S motif in the presence of cyclophilin hCyp‐18—an important peptidyl‐prolyl isomerase—was investigated. Increasing glutathione (GSH) concentrations were used to dissociate [A⋅ReVO⋅B] complexes that displayed low affinity for hCyp‐18. Conversely, coordinates that displayed submicromolar affinities for hCyp‐18 were protected against thiol exchange and could be detected by LC‐MS. Determination of the GSH concentration that decreased the extracted ionic current of the complex by 50 % (CC50) enabled the selection of three oxorhenium coordinates that were shown to bind to the active site of hCyp‐18 and to inhibit its peptidyl–prolyl isomerase activity in the micromolar to submicromolar range.

CHEMO-ENZYMIC SYNTHESIS OF PROTECTED CYANO DERIVATIVES OF GLUTAMATE

Abstract (2S,4RS)-Boc-4-cyanoglutamate γ-methyl ester (ee = 95%) and (2S)-Boc-2-amino-4-bis(cyano)butyrate (ee = 96%) were synthesised in respectively 43% and 40% overall yields by addition of sodium malonate derivatives onto Boc-dehydroalanine methyl ester followed by regio- and stereoselective hydrolysis of α-methyl ester by α-chymotrypsin. These regio-and stereoselectivities were strongly dependent on the nature of the γ-substituents.

Synthesis of phosphinic alanyl-proline surrogates Alaψ(PO2R-CH)Pro as potential inhibitors of the human cyclophilin hCyp-18

Abstract Pseudopeptides containing the phosphinic analogue of the alanyl-proline motif Alaψ(PO 2 R-CH)Pro, were synthesized via three- (R=H) and four-step (R=CH 3 ) procedures. The mixtures of diastereomers were evaluated as inhibitors of the human cyclophilin hCyp-18, an important peptidyl-prolyl isomerase.

Oxorhenium-Mediated Assembly of Noncyclic Selective Integrin Antagonists: A Combinatorial Approach

The parallel oxorhenium‐mediated assembly of 288 noncyclic RGD analogues is reported. All complexes contain a NS2+S chelating motif that enables the unambiguous coordination of the oxorhenium and oxotechnetium cores. In this study, “modules S” contain a variety of pending guanidinium groups whereas the “NS2 modules” are made of a series of N‐acylated amino acids. Combination of sets of “NS2” and “S modules” together with tetrabutylammonium tetrachlorooxorhenate gave the corresponding oxorhenium complexes in good yields and satisfactory purities. Evaluation of these metalloconstructs towards integrins αVβ3, αIIbβ3, and αVβ5 led to the identification of micromolar and submicromolar antagonists of theses integrins. These compounds exhibit interesting selectivities and promise attractive applications for the molecular imaging of integrin‐dependent pathologies.

Chelate oxorhenium to assemble new integrin antagonists

Assembly of independent chemical modules through oxorhenium coordination by a NS(2)+S chelation motif was applied to the synthesis of RGD (Arg-Gly-Asp) analogs. Modules were assembled through oxorhenium chelation to give a series of 18 metal complexes in good yields and satisfactory purities. Screening of these oxorhenium coordinates as antagonists of integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 3 bioactive compounds that exhibit submicromolar affinities for the 3 integrins. Preliminary studies showed that the corresponding oxotechnetium complexes are stable in mice plasma and therefore could be proposed for the molecular imaging of pathologies that overexpress integrins αVβ3 and αVβ5.