title: Gadolinium texaphyrin-methotrexate conjugates. Towards improved cancer chemotherapeutic agents.
abstract: Conjugates between methotrexate (MTX, Matrex, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-l-glutamic acid), an antifolate cancer chemotherapeutic to which resistance is often observed, and motexafin gadolinium (MGd), an experimental agent demonstrating selective tumor localization, are described. These systems were prepared in order to test whether linking these two species would produce agents with enhanced activity relative to MTX alone. Both ester- and amide-linked conjugates were synthesized starting from MGd and MTX. The ester conjugate showed greater in vitro anti-proliferative activity against the A549 lung carcinoma cell line at short incubation times than did MTX alone. Neither the amide conjugate, nor MGd, showed any observable activity under these in vitro conditions. These results are rationalized in terms of enhanced cellular uptake of both the ester and amide conjugates that is coupled with an effective rate of release (e.g., inherent or enzyme-mediated hydrolysis) in the case of the ester-linked conjugate, but not the corresponding amide system.
authors.affiliation: Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, 1 University Station-A5300, The University of Texas at Austin, Austin, Texas 78712-0165, USA.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Wei
authors.forename: Mark
authors.initials: M
authors.lastname: Fountain
authors.forename: Darren
authors.initials: D
authors.lastname: Magda
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Phil
authors.initials: P
authors.lastname: Lecane
authors.forename: Mimi
authors.initials: M
authors.lastname: Mesfin
authors.forename: Dale
authors.initials: D
authors.lastname: Miles
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Sessler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms; D008665:Metalloporphyrins / Q000737:chemistry* / Q000494:pharmacology; D008727:Methotrexate / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C437683:motexafin gadolinium; D008727:Methotrexate