A new type of mixed anhydride and its applications to the synthesis of 7-substituted 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazines with in vitro antitumor activity.
A new series of 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine derivatives 8-25 with heteroaryloxycarbonyl or heteroarylcarbamoyl substituents at position 7 have been synthesized as potential antitumor agents. In this procedure a novel type of mixed anhydride 7 was prepared from 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylic acid 6 and methanesulfonyl chloride, which in turn was condensed either with heteroarylamines or heteroarylhydroxy compounds. All the compounds prepared were screened at the National Cancer Institute (NCI) for their activities against a panel of 60 tumor cell lines, and relationships between structure and antitumor activity in vitro are discussed. The amides 8, 10, 12, 13, 21, and ester 25 were inactive, whereas the other compounds exhibited rather moderate activity against one or more human tumor cell lines. The prominent compound with remarkable activity (log GI(50) < -8) and selectivity for the leukemia HL-60(TB) cell line was 2-methyl-8-quinolyl 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylate 24.
Brzozowski
Zdzisław
Z
Department of Chemical Technology of Drugs, Medical University of Gdańsk, 80-416 Gdańsk, Poland.
Saczewski
Franciszek
F
D000812:Anhydrides / Q000138:chemical synthesis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008698:Mesylates / Q000737:chemistry; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C446056:2-methyl-8-quinolyl 8-chloro-5,5-dioxoimidazo(1,2-b)(1,4,2)benzodithiazine-7-carboxylate; D000812:Anhydrides; D000970:Antineoplastic Agents; D003499:Cyclic S-Oxides; D006575:Heterocyclic Compounds, 3-Ring; D008698:Mesylates; D013843:Thiazines; C030209:methanesulfonyl chloride