title: Rational design, synthesis and characterization of potent, drug-like monomeric Smac mimetics as pro-apoptotic anticancer agents.
abstract: A set of phenyl-substituted Smac mimetics/IAP inhibitor analogues of lead compound 2a was synthesized, aiming to retain its strong cell-free potency while increasing its bioavailability. Seventeen compounds 2b-r were prepared and characterized in vitro, using cell-free and cellular assays. Among them, the p-CF(3) substituted analogue 2m showed the best permeability through cell membranes, and was selected for further in vitro and in vivo studies due to its strong, sub-micromolar cellular potency.
authors.affiliation: CISI scrl, Via Fantoli 16/15, I-20138 Milan, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Bianchi
authors.forename: Marcello
authors.initials: M
authors.lastname: Ugazzi
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrante
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
authors.forename: Cinzia
authors.initials: C
authors.lastname: Scavullo
authors.forename: Eloise
authors.initials: E
authors.lastname: Mastrangelo
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D057786:Peptidomimetics