title: Synthesis of the orally macrofilaricidal and stable glycerolipidic prodrug of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl ycerol.
abstract: A new strategy is presented to develop macrofilaricidal compounds orally administered and able to concentrate in the lymphatic system. A diglyceride derivative of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl y cerol, was synthesized. The esterification of melphalan by 1,3-dipalmitin allowed chemical stabilization of the alkylating agent in aqueous dispersion. No degradation of this prodrug was observed after a 3-month storage of an aqueous dispersion at 4 degrees C. The filaricidal activity of the prodrug was compared with those of melphalan in vitro against adults, infective larvae and microfilariae of Molinema dessetae, and evaluated in vivo on Molinema dessetae infected Proechimy oris. In vitro, melphalan and the glycerolipidic prodrug were inactive against microfilariae but active at 1 mmol/l against infective larvae and adults. In vivo studies were performed with rodents subcutaneously inoculated with infective larvae from Aedes aegypti. The number of macrofilariae was significantly reduced following treatment with a single oral dose of the alkylating agent prodrug (0.082 mmol/kg).
authors.affiliation: Laboratoire de Physicochimie des Surfaces et Innovation en Pharmacotechnie, Université de Paris XI, Chatenay-Malabry, France.
authors.forename: J R
authors.initials: JR
authors.lastname: Deverre
authors.forename: P
authors.initials: P
authors.lastname: Loiseau
authors.forename: F
authors.initials: F
authors.lastname: Puisieux
authors.forename: P
authors.initials: P
authors.lastname: Gayral
authors.forename: Y
authors.initials: Y
authors.lastname: Letourneux
authors.forename: P
authors.initials: P
authors.lastname: Couvreur
authors.forename: J P
authors.initials: JP
authors.lastname: Benoit
mesh_terms: D000330:Aedes; D000818:Animals; D004075:Diglycerides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005368:Filariasis / Q000188:drug therapy / Q000469:parasitology; D005369:Filaricides / Q000138:chemical synthesis*; D007814:Larva / Q000187:drug effects; D008297:Male; D008558:Melphalan / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008842:Microfilariae / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012377:Rodentia
chemical_list: D004075:Diglycerides; D005369:Filaricides; D011355:Prodrugs; C078008:1,3-dipalmitoyl-2-(4'-(bis(2''-chloroethyl)amino)phenylalaninoyl)glycerol; D008558:Melphalan