Synthesis and cytotoxicity evaluation of 6,11-dihydro-pyridazo- and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-diones.
The 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione derivatives were synthesized from 6,7-dichloro-5,8-phthalazinedione and 6,7-dichloro-5,8-quinolinedione, respectively, producing a series of new anticancer drugs. The cytotoxic activities of the prepared compounds were evaluated by a SRB (Sulforhodamine B) assay against the following tumor cell lines: A459 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), XF498 (human CNS), and HCT 15 (human colon). Almost all the derivatives of the 6,11-dihydro-pyridazo[2[,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione, tetracyclic heteroquinone analogues with four or three nitrogen atoms, exhibited excellent cytotoxicity on almost all the human tumor cell lines tested. Specifically, 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione (4a) exhibited potent activity against all the tumor cell lines, and in particular, its cytotoxic effect against HCT 15 (ED(50)=0.004 microg/mL) was 25 times greater than that of doxorubicin (ED(50)=0.093 microg/mL).
Lee
Hyun-Jung
HJ
Division of Medicinal Chemistry, College of Pharmacy, Ewha Woman's University, Seoul 120-750, South Korea.
Kim
Jin Sung
JS
Park
Se-Young
SY
Suh
Myung-Eun
ME
Kim
Hwa Jung
HJ
Seo
Eun-Kyung
EK
Lee
Chong-Ock
CO
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010619:Phenazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012235:Rhodamines / Q000737:chemistry; D013329:Structure-Activity Relationship
C493131:6,11-dihydro-pyridazo(2,3-b)phenazine-6,11-dione; C493130:6,11-dihydro-pyrido(2,3-b)phenazine-6,11-dione; C493125:6,7-dichloro-5,8-phthalazinedione; C493127:6,7-dichloro-5,8-quinolinedione; D000970:Antineoplastic Agents; D010619:Phenazines; D010793:Phthalazines; D011804:Quinolines; D012235:Rhodamines; C022027:lissamine rhodamine B