title: Lipophilic conjugates of methotrexate with short-chain alkylamino acids as DHFR inhibitors. Synthesis, biological evaluation, and molecular modeling.
abstract: Pursuing previous researches on lipophilic conjugates of methotrexate, aimed at over-crossing a form of transport resistance shown by some tumor cell lines toward the drug, a new series of derivatives is described in which the drug alpha- and gamma-carboxyl groups have been linked through amide bonds to short-chain alpha-alkylamino acids (4-6 carbon atoms). A specific NMR study was performed to delineate the stereochemistry of the conjugates. The inhibitory activity of these compounds against the target enzyme, (bovine liver) dihydrofolate reductase, and a sensitive (CCRF-CEM) and a transport-resistant tumor cell subline (CEM-MTX) were assessed. The conjugates showed the ability of retaining the same inhibitory activity also against the resistant cell subline, against which the parent drug was much less active than against the wild one; the alpha,gamma-bis(hexyl) derivative was the most active term of the series. Docking studies are in agreement with the proposed mode of interaction of these conjugates with the human DHFR.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Catania, Viale A. Doria 6, Città Universitaria, I-95125 Catania, Italy. r.pignatello@unict.it
authors.forename: Rosario
authors.initials: R
authors.lastname: Pignatello
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.forename: Stefano
authors.initials: S
authors.lastname: Forte
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Giacomo
authors.forename: Valeria
authors.initials: V
authors.lastname: Sorrenti
authors.forename: Luisa
authors.initials: L
authors.lastname: Vicari
authors.forename: Gloria
authors.initials: G
authors.lastname: Uccello Barretta
authors.forename: Federica
authors.initials: F
authors.lastname: Balzano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Puglisi
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000502:physiology; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D008958:Models, Molecular; D013237:Stereoisomerism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D008055:Lipids; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate