title: Antifolate and antiproliferative activity of 6,8,10-triazaspiro[4.5]deca-6,8-dienes and 1,3,5-triazaspiro[5.5]undeca-1,3-dienes.
abstract: Two series of triazaspiroalkanedienes, bearing a substituted phenoxy propyloxy side chain, were identified as potent mammalian DHFR inhibitors. One series has a 6,5-spiro bicyclic ring system and the other series has a 6,6-spiro bicyclic system. Both series were synthesized and tested for in vitro mammalian DHFR inhibitory activity and antiproliferative activity against A549 human lung-cancer cells. Compound 3c showed the highest antiproliferative activity against A549 cells with an IC(50) value of 27.1nM. Rescue experiment confirmed its antifolate antiproliferative mechanism. The excellent antifolate and antiproliferative activity of selected analogues presented in this study warrants further investigation as potential leads in the anticancer drug discovery.
authors.affiliation: Department of Pharmacy, Faculty of Science, 18 Science Drive 4, National University of Singapore, Singapore 117543, Singapore. maxwellcn@yahoo.com
authors.forename: Xiang
authors.initials: X
authors.lastname: Ma
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C548621:1,3,5-triazaspiro(5.5)undeca-1,3-diene; C548620:6,8,10-triazaspiro(4.5)deca-6,8-diene; D000970:Antineoplastic Agents; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013141:Spiro Compounds; D013762:Tetrahydrofolate Dehydrogenase