Synthesis of Pyridino[2,3-f]indole-4,9-dione derivatives and evaluation on their cytotoxic activity

Abstract

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).