Synthesis and antitumor cytotoxicity evaluation of pyrido[4,3,2-de]quinolines and isoquinolino[6,5,4,3-cde]quinolines.
A series of novel pyrido[4,3,2-de]quinoline and isoquinolino[6,5,4,3-cde] quinoline compounds was synthesized and evaluated for cytotoxicity in the National Cancer Institute developmental therapeutics program. The tricyclic compound 7 was synthesized by the cyclization of 3,4-diamino-1,2dimethoxybenzene with diethyl 1,3-acetonedicarboxylate. Oxidation of monochloropyrido[4,3,2-de]quinoline 8 selectively produced 2,3-diketopyrido[4,3,2-de]quinoline 9 as deep violet crystals. Compound 9, when treated with acetone or acetophenone, affords the tetracyclic isoquinolino[6,5,4,3-cde]quinolines 13 and 14, respectively. 2,3-Diketopyrido[4,3,2-de]quinolines 9 and 10 exhibit higher cytotoxic potency than isoquinolino[6,5,4,3-cdelquinolines 13, 14, 15 and 16. Compound 9 selectively affects the cell growth against leukemia CCRF-CEM and HL-60 cell lines, the non-small cell lung cancer HOP-92 cell line, and breast cancer MDA-MB231/ ATCC and MDA-MB- 435 cell lines with GI(50) values of <2.0 microM. Modification of compound 9 with an ester group at the N-1 position afforded compound 10, which exhibits a wide spectrum of anticancer activities with a mean graph midpoint value of 1.8 microM against the 60 cancer cell lines.
Ding
Q
Q
Department of Chemistry, University of Alberta, Edmonton, Canada.
Jia
G
G
Lown
J W
JW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D007938:Leukemia; D008175:Lung Neoplasms; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007546:Isoquinolines; D011804:Quinolines