title: Peptide T-araC conjugates: solid-phase synthesis and biological activity of N4-(acylpeptidyl)-araC.
abstract: Due to the capability of peptidyl derivatives of araC to behave as prodrugs of this antimetabolite, and because of the well known biological properties of peptide T and its analogues (in particular that of targeting CD4+ cells), new peptide T-araC conjugates were prepared and tested in vitro for antiproliferative activity. The aim was that of specifically delivering the antitumor drug to CD4+ cells. N4-(Acylpeptidyl)-derivatives of araC were synthesized by a new general approach involving solid-phase synthesis, which allows mild conditions, avoids the usually required protection of the glycoside portion of nucleosides and affords high yields of the final products. After the demonstration that peptide T-araC conjugates were able to activate chemotaxis by binding CD4 receptor on monocyte membranes, the antiproliferative activity was evaluated against a panel of leukemia lymphoma and carcinoma cell lines derived from human tumors, three CD4+ cell lines included. Title compounds resulted effective as antiproliferative agents at concentrations 4- to 10-fold higher than those of araC alone, did not preferentially inhibit CD4+ cells and proved stable not only in cell culture medium containing 20% FCS, but also in human plasma. All this suggests their potential utility in vivo.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Manfredini
authors.lastname: Marastoni-M
authors.forename: R
authors.initials: R
authors.lastname: Tomatis
authors.forename: E
authors.initials: E
authors.lastname: Durini
authors.forename: S
authors.initials: S
authors.lastname: Spisani
authors.forename: A
authors.initials: A
authors.lastname: Pani
authors.forename: T
authors.initials: T
authors.lastname: Marceddu
authors.forename: C
authors.initials: C
authors.lastname: Musiu
authors.forename: M E
authors.initials: ME
authors.lastname: Marongiu
authors.forename: P
authors.initials: P
authors.lastname: La Colla
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens; D002455:Cell Division / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003561:Cytarabine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D009000:Monocytes / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D015717:Peptide T / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D015704:CD4 Antigens; D004337:Drug Carriers; D009842:Oligopeptides; D011355:Prodrugs; D003561:Cytarabine; D015717:Peptide T; D010447:Peptide Hydrolases