title: Synthesis of 2,8-disubstituted imidazo[1,5-a]pyrimidines with potent antitumor activity.
abstract: Seventeen 1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine derivatives bearing electron-withdrawing substituents were designed and synthesized by novel ring closure as potential antitumor agents. They were screened for their activities against mouse leukemia L1210 and human oral epidermoid carcinoma KB cell lines, and relationships of structure and antitumor activity in vitro are discussed. It was found that 8-thiocarbamoyl-1,2,3,4-tetrahydroimidazo[1, 5-a]pyrimidin-2(1H)-thione (8c) exhibited activity comparable to that of 5-fluorouracil against both L1210 and KB cells. The existence of both 2-thioxo and 8-substituent with a thioxo group in the molecule is crucial for the cytotoxicity against L1210 and KB cells. A novel procedure for introduction of a double bond between C-3 and C-4 in 8c was developed. Introduction of the 3,4-double bond increased the activity against L1210, but against KB cells the activity decreased by 4-fold. Cytotoxicity of compounds 8c and 8-thiocarbamoyl-1,2-dihydroimidazo[1,5-a]pyrimidin-2(1H)-thione (11c) against human solid tumor and leukemia cell lines was further evaluated. The saturation of the 3,4-double bond led to a significant increase in cytotoxicity against tumor cell lines tested.
authors.affiliation: Research Laboratory, Minophagen Pharmaceutical Company, 2-2-3 Komatsubara, Zama 228-0002, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: N
authors.initials: N
authors.lastname: Nagata
authors.forename: H
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Y
authors.initials: Y
authors.lastname: Mizuno
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C119082:8-thiocarbamoyl-1,2,3,4-tetrahydroimidazo(1,5-a)pyrimidin-2(1H)-thione; C119083:8-thiocarbamoyl-1,2-dihydroimidazo(1,5-a)pyrimidin-2(1H)-thione; D000970:Antineoplastic Agents; D007093:Imidazoles; D011743:Pyrimidines