title: Lipophilic methotrexate conjugates with antitumor activity.
abstract: Lipophilic methotrexate (MTX)-lipoamino acid conjugates coupled with amide or ester linkages (1a-1r) were synthesised. The inhibitory activity of the conjugates was evaluated on bovine liver DHFR. The in vitro growth inhibitory effect against MTX-sensitive human lymphoblastoid CCRF-CEM cells and an MTX-resistant sub-line (CEM/MTX), which displays defective intracellular transport of MTX, was determined under short-term and continuous (120-h incubation) exposure conditions. The alpha, gamma, or alpha,gamma amide conjugates showed different activity in inhibiting the growth of parent cells. CEM/MTX cells were much less susceptible than CCRF-CEM cells to inhibition by alpha or alpha,gamma-substituted lipoamino acid conjugates, whereas both cell lines were almost equally sensitive to the MTX-gamma conjugates. Although less potent than MTX, they could partially circumvent the impaired transport system. These findings confirm that lipophilic MTX conjugates may be good lead compounds on the drug development for the treatment of some MTX-resistant tumors. Ester-type conjugates displayed an interesting activity against parent CCRF-CEM cells, although they were less potent against the transport-resistant sub-line. Stability studies on these molecules indicated that they are not degraded into MTX in the culture medium, thus suggesting that they are not able to over-cross cell resistance despite of their lipophilicity.
authors.affiliation: Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, UK. pignatel@mbox.unict.it
authors.forename: R
authors.initials: R
authors.lastname: Pignatello
authors.forename: G
authors.initials: G
authors.lastname: Spampinato
authors.forename: V
authors.initials: V
authors.lastname: Sorrenti
authors.forename: C
authors.initials: C
authors.lastname: Di Giacomo
authors.forename: L
authors.initials: L
authors.lastname: Vicari
authors.forename: J J
authors.initials: JJ
authors.lastname: McGuire
authors.forename: C A
authors.initials: CA
authors.lastname: Russell
authors.forename: G
authors.initials: G
authors.lastname: Puglisi
authors.forename: I
authors.initials: I
authors.lastname: Toth
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005079:Excipients; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D013058:Mass Spectrometry; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D005079:Excipients; D005493:Folic Acid Antagonists; D008055:Lipids; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate