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Synthesis of Pyridino[2,3-f]indole-4,9-dione derivatives and evaluation on their cytotoxic activity
- Synthesis of Pyridino[2,3-f]indole-4,9-dione derivatives and evaluation on their cytotoxic activity
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- 이화여자대학교 대학원
- Streptonigrin has been used clinically as anticancer drug, but its use has been limited by its toxicity.
We report upon the synthesis of the following derivatives: N-substituted-pyridino[2,3-f]indole-4,9-dione, 6-(α-diethoxycarbonyl-methyl)-7-substituted-amino-quinoline-5,8-dione, dihydro-N-substituted-pyridino[2,3-f]indole-2,4,9-trione and 4a,7,11-triazα-benzo[3,2-a]fluorene-5,6-dione which contain the active quinoline-5,8-dione(XVII) moiety.
When the 7-chloro-6-(α-diethoxycarbonyl-methyl)-quinoline-5,8-dione(I-A) was reacted with alkyl amines, such as, methyl-, ethyl-, propyl-, n-butyl-, isopropyl-, ethanol-, β-methoxyethyl-, cyclopropyl-, benzyl- and cyclohexyl-, and aniline, the corresponding 3-ethoxycarbonyl-2-hydroxy-N-substituted-pyridino[2,3-f]indole-4,9-dione(A) derivatives were obtained. The 7-chloro-6-(α-diethoxycarbonyl-methyl)-quinoline-5,8-dione(I-A) and aryl amines, including, p-toluidine, m-toluidine, o-toluidine, 4-methoxyaniline and 4-ethoxyaniline, were reacted to yield the 6-(α-diethoxycarbonyl-methyl)-7-substituted-amino-quinoline-5,8-dione(B) derivatives. Similarly, 6-(α-diethoxycarbonyl-ethyl)-7-chloroquinoline-5,8-dione(I-C) was reacted with alkyl amines, such as, methyl-, ethyl- and propyl- and afforded 2,3-dihydro-3-methyl-1N-substituted-pyridino [2,3-f] indole-2, 4,9-trione derivatives(C).
Reaction of 6,7-dichloro-5,8-quinolinedione(XVII) with 2-aminopyridine derivatives, including 2-amino-4-methyl-pyridine and 2-amino-5-methyl-pyridine, produced 4a,7,11-triazabenzo[3,2-a]fluorene-5,6-dione derivatives(D).
The cytotoxic activities of these compounds have been tested in SRB(SulfoRhodamine B) assays against the cancer cell lines of A-549(human lung cancer), SK-MEL-2(human melanoma cancer), SK-OV-3(human ovarian cancer), XF-498(human brain cancer) and HCT 15(human colon cancer). This testing revealed that some of these compounds 6-(α-diethoxycarbonyl-ethyl)-7-chloroquinoline-5,8-dione(I-C), 3-ethoxycarbonyl-2-hydroxy-N-(β-hydroxyethyl)-pyridino[2,3-f]indole-4,9-dione(A-6), 6-(α-diethoxy-carbonyl-methyl)-7-(3-methyl-phenylamino)-quinoline-5,8-dione(B-2), 6-(α-diethoxy-carbonyl-methyl)-7-(4-ethoxy-phenylamino)-quinoline-5,8-dione(B-5), and N-butyl-3-ethoxycarbonyl-2-hydroxy-pyridino[2,3-f]indole-4,9-dione(A-4) had significant cytotoxic effects compared with cis-platin, to these human tumor cell lines. Compound I-A exhibited higher and similar cytotoxic activities than cis-platin in these human tumor cell lines. The compound, N-benzyl-3-ethoxycarbonyl-2-hydroxy-pyridino[2,3-f]indole-4,9-dione(A-9), also showed higher activity than cis-platin. The highest level of cytotoxic activity in these human tumor cell lines was observed in the compound 6-(α-diethoxycarbonyl-methyl)-7-(2-methyl-phenylamino)-quinoline-5,8-dione(B-3).
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