title: Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting α(v)β(3)/α(v)β(5) integrins and IAP proteins.
abstract: The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin αvβ3/αvβ5 ligand portion and a pro-apoptotic SMAC mimetic portion (cyclo-RGD/SMAC mimetic conjugates) are reported. The binding strength of the two separate units is generally maintained by these dual action conjugates. In particular, the connection between the separate units (anchor points on each unit; nature, length and stability of the linker) influences the activity of each portion against its molecular targets (integrins αvβ3/αvβ5 for cyclo-RGD, IAP proteins for SMAC mimetics). Each conjugate portion tolerates different substitutions while preserving the binding affinity for each target.
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, Via Golgi 19, I-20133, Milan, Italy. pierfausto.seneci@unimi.it cesare.gennari@unimi.it.
authors.forename: M
authors.initials: M
authors.lastname: Mingozzi
authors.forename: L
authors.initials: L
authors.lastname: Manzoni
authors.forename: D
authors.initials: D
authors.lastname: Arosio
authors.forename: A
authors.initials: A
authors.lastname: Dal Corso
authors.forename: M
authors.initials: M
authors.lastname: Manzotti
authors.forename: F
authors.initials: F
authors.lastname: Innamorati
authors.forename: L
authors.initials: L
authors.lastname: Pignataro
authors.forename: D
authors.initials: D
authors.lastname: Lecis
authors.forename: D
authors.initials: D
authors.lastname: Delia
authors.forename: P
authors.initials: P
authors.lastname: Seneci
authors.forename: C
authors.initials: C
authors.lastname: Gennari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D019921:Biotinylation / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D002474:Cell-Free System; D019281:Dimerization; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008024:Ligands; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019030:Receptors, Vitronectin / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D039302:Integrin alphaVbeta3; D008024:Ligands; D024101:Mitochondrial Proteins; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; D019096:Vitronectin; C507169:cyclic arginine-glycine-aspartic acid peptide; C064660:integrin alphaVbeta5; D004317:Doxorubicin