Chemoselectively addressable template: a valuable tool for the engineering of molecular conjugates.
We herein report the modular design and the synthesis of new molecular conjugates, which can combine a cell targeting function (ligand domain) with potential cytotoxic molecules (effector domain). The present approach utilizes a cyclic peptide template, Chemoselectively Addressable Template (CAT) as a key intermediate. These CAT molecules exhibit two independent and chemically addressable domains which permits the sequential and regioselective assembly of different ligand and/or effector domains. The attachment of various units to the template was achieved by the formation of iterative oxime bonds. The chemoselective oxime bonds were produced by the reaction of glyoxylyl aldehyde groups obtained from serine precursors. The process was further developed to prevent transoximation reactions. RAFT(c[-RGDfK-])4, a synthetic vector targeting the tumor-associated a alpha(V)beta3 integrin was prepared and coupled to either a cytotoxic peptide or oligonucleotide as an illustration of present approach. The potential application of this approach has been further demonstrated by the synthesis of high molecular weight compounds such as RAFT(c[-RGDfK-])16, a alpha(V)beta3-targeting ligand of high valency index.
Garanger
Elisabeth
E
LEDSS, UMR CNRS 5616, ICMG FR-2607, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
Boturyn
Didier
D
Renaudet
Olivier
O
Defrancq
Eric
E
Dumy
Pascal
P
D000447:Aldehydes / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008024:Ligands; D008968:Molecular Conformation; D010091:Oximes / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D013499:Surface Properties
D000447:Aldehydes; D039302:Integrin alphaVbeta3; D008024:Ligands; D010091:Oximes; D010456:Peptides, Cyclic; C516394:cyclic(RGDfK)16 peptide