Cyclic aza-peptide integrin ligand synthesis and biological activity

Aza-peptides are obtained by replacement of the α-C-atom of one or more amino acids by a nitrogen atom in a peptide sequence. Introduction of aza-residues into peptide sequences may result in unique structural and pharmacological properties, such that aza-scanning may be used to probe structure-activity relationships. In this study, a general approach for the synthesis of cyclic aza-peptides was developed by modification of strategies for linear aza-peptide synthesis and applied in the preparation of cyclic aza-pentapeptides containing the RGD (Arg-Gly-Asp) sequence. Aza-amino acid scanning was performed on the cyclic RGD-peptide Cilengitide, cyclo[R-G-D-f-N(Me)V] 1, and its parent peptide cyclo(R-G-D-f-V) 2, potent antagonists of the αvβ3, αvβ5, and α5β1 integrin receptors, which play important roles in human tumor metastasis and tumor-induced angiogenesis. Although incorporation of the aza-residues resulted generally in a loss of binding affinity, cyclic aza-peptides containing aza-glycine retained nanomolar activity toward the αvβ3 receptor.     

N-Aminosulfamide peptide mimic synthesis by alkylation of aza-sulfurylglycinyl peptides

N-Aminosulfamides are peptidomimetics in which the C(α)H and the carbonyl of an amino acid residue are both respectively replaced by a nitrogen atom and a sulfonyl group. Aza-sulfurylglycinyl tripeptide analogs were effectively synthesized from amino acid building blocks by condensations of N-protected amino hydrazides and p-nitrophenylsulfamidate esters. The installation of N-alkyl chains and access to other aza-sulfuryl amino acid residues were effectively achieved by chemoselective alkylation.     

Solid-phase synthesis of 3-aminopyrrole-2,5-dicarboxylate analogues

An efficient strategy has been developed for the solid-phase parallel synthesis of 3-aminopyrrole-2,5-dicarboxylate analogues. A library of twenty-nine 2,3,5-trisubstituted pyrroles has been synthesized on Wang resin by a 5-6 step process. The attachment of (2S,4R)-4-hydroxy-N-(PhF)proline cesium salt (PhF = 9-(9-phenylfluorenyl)) to Wang bromide resin, followed by alcohol oxidation, produced the resin-bound 4-oxo-N-(PhF)prolinate as the pyrrole precursor. Resin-bound 3-aminopyrroles were synthesized by treatment of the oxo-N-(PhF)prolinate resin with different secondary amines and diversified at the 2-position by acylation with trichloroacetyl chloride and haloform reactions with primary amines. 3-Aminopyrrole-2,5-dicarboxylates were isolated in 81-99% purity and 51-99% yields after cleavage from the resin using TFA or sodium methoxide.     

9-(4-Bromophenyl)-9-fluorenyl as a safety-catch nitrogen protecting group

[reaction: see text] The 9-(4-bromophenyl)-9-fluorenyl (BrPhF) group has been developed as a novel safety-catch amine protection. This relatively acid-stable protecting group can be successfully activated by palladium-catalyzed cross-coupling reaction of the aryl bromide with morpholine and then cleaved effectively under mild conditions using dichloroacetic acid and triethylsilane. Complementary conditions are reported for selective removal of the BrPhF group in the presence of tert-butyl esters and carbamates as well as deprotection of tert-butyl esters and carbamates in the presence of BrPhF amines.     

4-alkoxy- and 4-amino-2,2'-bipyrrole synthesis

[Structure: see text] 4-alkoxy-2,2'-bipyrroles and the first examples of 4-amino-2,2'-bipyrroles have been synthesized by a diversity-oriented strategy from 4-hydroxyproline. The bipyrrole products offer interesting potential as building blocks for making pyrrole products, as demonstrated by the first synthesis of an amino prodigiosin analogue.     

Conjugated C3 symmetric aryl tripyrroles and aryl bipyrroles: synthesis,optical and electronic properties

Conjugated C₃ symmetric molecules have been pursued for their fluorescent and electrochemical properties. The synthesis of conjugated C₃ symmetric aryl tripyrroles has been performed by a route featuring three steps from trimethyl 1,3,5-benzene tricarboxylate 6: copper-catalyzed cascade addition of vinylmagnesium bromide to convert the carboxylates into γ,δ-unsaturated ketones, Tsuji–Wacker olefin oxidations to form tris(1,4-dione) 9, and Paal–Knorr condensation with ammonia and different amines to furnish the final tripyrroles (30–60% yields). In addition, incomplete reaction of vinylmagnesium bromide to 6 provided benzoate 8 possessing two γ,δ-unsaturated ketones, which were similarly converted to 3,5-dipyrrolylbenzoates 11. The absolute fluorescence quantum yields (Φ_fl) and electrochemical properties of 5a–c and 11a–c were investigated. The Φ_fl are the first reported for such compounds and they ranged between 2 and 40%, contingent on structure and solvent polarity. Cyclic voltammetry revealed that the compounds could be both oxidized and reduced, albeit irreversibly. The oxidation potentials (E_ox) varied between 0.73 V and 1.2 V and the reduction potentials (E_red) varied from −0.83 V to −1.36 V. The lowest redox processes were measured for the NH–pyrrole 5a. Moreover, tripyrrole 5a was air stable and on oxidative doping with ferric chloride exhibited a 50 nm bathochromic shift in its absorbance spectrum.     

Large structural modification with conserved conformation: analysis of delta(3)-fused aryl prolines in model beta-turns

For the first time, the influence of a fused Delta3-arylproline on peptide conformation has been studied by the synthesis and comparison of the conformations of peptides containing proline and pyrrolo-proline, 3 (PyPro). Pyrrolo-proline was demonstrated to be a conservative replacement for Pro in model beta-turns, 4 and 5, as shown by their similar DMSO titration curves, cis/trans-isomer populations, and NOESY spectral data. Pyrrolo-proline may thus be used for studying the structure activity relationships of Pro-containing peptides with minimal modification of secondary structures.     

Rigid dipeptide mimics: synthesis of enantiopure C6-functionalized pyrrolizidinone amino acids

Enantiopure (3S,5S,6R,8S)- and (3S,5S,6S,8S)-6-hydroxypyrrolizidinone 3-N-(Boc)amino 8-methyl carboxylates (6R)- and (6S)-1 were synthesized in seven steps starting from (2S)-alpha-tert-butyl N-(PhF) aspartate beta-aldehyde (10). Carbene-catalyzed acyloin condensation of beta-aldehyde 10 followed by acetylation provided a separable mixture of diastereomeric (2S,5RS,7S)-diamino-4-oxo-5-acetoxysuberates (13). Reductive amination and lactam annulation of the respective alpha-acetoxy ketones 13 provided hydroxypyrrolizidinones (6R)- and (6S)-1 with retention of the C6-position stereochemistry. The X-ray crystallographic study of (6R)-1 indicated dihedral angles constrained within the heterocycle that were consistent with the ideal values for the i + 1 and i + 2 residues of a type II' beta-turn. Hydrogen-bonding studies on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamides (6R)- and (6S)-21 in DMSO-d6, demonstrated different NH chemical shift displacements and temperature coefficients for the amide and carbamate protons, indicative of solvent shielded and exposed hydrogens in a turn conformation. 6-Hydroxy pyrrolizidinone amino carboxylate 1 may thus find application as a constrained alaninylhydroxyproline dipeptide mimic. In addition, alkylation of the hydroxyl group provided orthogonally protected pyrrolizidinone amino dicarboxylate (6R)-25, demonstrating potential for expanding the diversity of these rigid dipeptide surrogates for the exploration of peptide conformation-activity relationships.     

Poly(vinyl alcohol)-graft-poly(ethylene glycol) resins and their use in solid-phase synthesis and supported TEMPO catalysis

New poly(vinyl alcohol)-graft-poly(ethylene glycol) (PVA-g-PEG) resins with various PEG chain lengths, which have high loadings and good swelling both in water and organic solvents, have been prepared via an anionic polymerization of ethylene oxide onto PVA beads and applied in solid-phase synthesis, supported TEMPO catalysis and in HR-MAS 1H NMR spectral analysis.