title: Novel folate-hydroxamate based antimetabolites: synthesis and biological evaluation.
abstract: A set of hydroxamate derivatives of folic acid and methotrexate (MTX) was synthesized and evaluated for the inhibitory activity against histone deacetylase (HDAC) and dihydrofolate reductase (DHFR), two enzymes overexpressed in metastasizing tumors. The synthesized compounds were further screened for their antiproliferative activity in two human cancer cell lines, A549 (non-small cell lung carcinoma) and PC-3 (prostate adenocarcinoma). All derivatives showed significant inhibitory activity against HDACs (micromolar range) while only the MTX derivative was reasonably effective in DHFR inhibition. A docking study provided insight into the binding mode of the most potent inhibitor in the active sites of the enzymes, allowing rationalization of the bioassays. The MTX-based compound could be of interest for testing against metastasizing tumors in an animal model. The studied derivatives represent promising molecular templates for further development of dual activity anti-cancer drugs.
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, 1049-001 Lisboa, Portugal.
authors.forename: Marta P
authors.initials: MP
authors.lastname: Carrasco
authors.forename: Eva A
authors.initials: EA
authors.lastname: Enyedy
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Krupenko
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Krupenko
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
mesh_terms: D000963:Antimetabolites / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005492:Folic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D008727:Methotrexate