title: Application of the Ugi reaction with multiple amino acid-derived components: synthesis and conformational evaluation of piperazine-based minimalist peptidomimetics.
abstract: The concurrent employment of α-amino acid-derived chiral components such as aldehydes and α-isocyanoacetates, in a sequential Ugi reaction/cyclization two-step strategy, opens the door to the synthesis of three structurally distinct piperazine-based scaffolds, characterized by the presence of L-Ala and/or L-Phe-derived side chains and bearing appropriate functionalities to be easily applied in peptide chemistry. By means of computational studies, these scaffolds have been demonstrated to act as minimalist peptidomimetics, able to mimic a well defined range of peptide secondary structures and therefore potentially useful for the synthesis of small-molecule PPI modulators. Preliminary biological evaluation of two different resistant hepatocellular carcinoma cellular lines, for which differentiation versus resistance ability seem to be strongly correlated with well defined types of PPIs, has revealed a promising antiproliferative activity for selected compounds.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy. alessandra.silvani@unimi.it.
authors.forename: Mattia
authors.initials: M
authors.lastname: Stucchi
authors.forename: Silvia
authors.initials: S
authors.lastname: Cairati
authors.forename: Rengul
authors.initials: R
authors.lastname: Cetin-Atalay
authors.forename: Michael S
authors.initials: MS
authors.lastname: Christodoulou
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pescitelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Silvani
authors.forename: Deniz Cansen
authors.initials: DC
authors.lastname: Yildirim
authors.forename: Giordano
authors.initials: G
authors.lastname: Lesma
mesh_terms: D000409:Alanine / Q000737:chemistry*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008968:Molecular Conformation; D057786:Peptidomimetics; D010649:Phenylalanine / Q000737:chemistry*; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D057786:Peptidomimetics; D010879:Piperazines; D000077489:Piperazine; D010649:Phenylalanine; D000409:Alanine