title: Peripheral benzodiazepine receptor ligand-melphalan conjugates for potential selective drug delivery to brain tumors.
abstract: To gain insight into the strategy to target PBR ligand-drug conjugates to brain tumors, novel N-imidazopyridinacetyl-melphalan conjugates and the corresponding ethyl esters have been prepared and evaluated for their cytotoxicity in melphalan-sensitive human (SF126, SF188) and rat (RG-2) glioma cell lines. These conjugates exhibited PBR binding affinity with IC(50) values ranging from 57 and 2614 nM. By a computational approach it can be predicted that these conjugates possess significant brain penetration. The stability of the conjugates in 0.05 M phosphate buffer at pH 7.4 and, in some cases, in dilute human serum solution was determined. All the ethyl ester derivatives were stable in 0.05 M phosphate buffer at pH 7.4 and their half-lives exceeded 28 h. Conversely, under the same conditions, the corresponding acids were found to undergo a fast cleavage within a few minutes. HPLC-MS analysis of the mixture from degradation in buffer and physiological medium of the representative cases allowed the identification of their main degradation products. A plausible degradation pathway accounting for the available experimental data is presented.
authors.affiliation: Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy. trapani@farmchim.uniba.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.forename: Andrea
authors.initials: A
authors.lastname: Latrofa
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ma
authors.forename: Karin
authors.initials: K
authors.lastname: Reed
authors.forename: Mariangela
authors.initials: M
authors.lastname: Serra
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
authors.forename: Gaetano
authors.initials: G
authors.lastname: Liso
authors.forename: James M
authors.initials: JM
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D008024:Ligands; D008558:Melphalan / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D015394:Molecular Structure; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D007546:Isoquinolines; D008024:Ligands; D008558:Melphalan; C037850:PK 11195