Imidazoquinolinedione 유도체의 합성 및 생리 활성 연구

Abstract

Streptomyces focculus에서 분리된 Streptonigrin은 여러 가지 종양을 저해하며 임상에서 항암제로 사용되고 있으나 독성 때문에 그 사용이 제한되어 왔다. 최근 발표된 Johnson연구진의 보고에 의하면 Streptonigrin의 모핵인 5,8-quinolinedione부분이 Streptonigrin보다 독성은 적으면서 더욱 강한 세포 독성을 나타내는 것으로 보고되었다. 따라서 본 실험에서는 분자내 고리화 반응을 통해 5,8-quinolinedione을 모핵으로 하여 3～4환의 imidazoquinolinedione 유도체를 합성하였다. 6-Acetamido-7-chloroquinoline-5,8-dione(4)에 지방족 아민 (methylamine ethylamine, propylamine, butylamine, β-chloroethylamine, benzylamine, β-hydroxyethylamine, isopropylamine)을 반응시켜 1-alkyl-2-methyl-imidazo [4,5-g]quinoline-4,9-dione(Ia-h)유도체를 얻었고, 방향족 아민 (aniline, 4-nitr-oaniline, 4-bromoaniline, 4-ethoxyaniline, 4-chloroaniline, 4-methylaniline, 4-trifluoroaniline을 반응시켜 1-aryl-2-methyl-imidazo[4,5-g]quinoline-4,9-dione(IIa-g)유도체를 얻었다. 또한 6,7-dichloroquinoline-5,8-dione(1)에 piperidine, morpholine, thiomor-pholine을 반응시켜 1,2,3,4-tetrahydropyrido[1,2-a]imidazo[4,5-g]quinoline-6,11-dione(IIIa), morpholino[1,2-a]imidazo[4,5-g]quinoline-6,11-dione(IIIb),thiomorpholino[1,2-a]imidazo[4,5-g]quinoline-6,11-dione(IIIc)을 합성하였다. 합성한 화합물들의 세포 독성 효능은 A549 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), IIIF 498 (human CNS), HCT 15 (human colon)의 cell lines에 SRB (SulfoRhodamin B) Assay로 측정하였으며, 3환의 imidazoquinolinedione(Ia-h, IIa-g)보다 4환의 imidazoqui-noline유도체(IIIa-c)들이 cell lines 모두에서 더 좋은 세포 독성 효과를 나타낸다는 결과를 얻었다. 이들 화합물의 항암성을 이론적으로 연구하기 위하여 DNA-Interaction energy(ΔΕ)와 logP(lipophilicity)을 SRB Assay 측정치 ED_50값과 비교해 본 결과 큰 상관성이 없는 것으로 나타났다. ; Streptonigrin isolated from Streptomyces focculus inhibits various tumors and is therefore of clinical interest in the treatment of neoplastic disease. However, because of its toxicity, its use has been limited as an anticancer agent. The recent Johnson s study has been carried out to clarify the contribution of the quinoline-5,8-dione, the moiety of Streptonigrin. Its derivatives have a strong tumor action and have a lower toxicity than Streptonigrin. Therefore, we have synthesized series of the ring-closed imidazoquinolinedione derivatives of the quinoline-5,8-dione as cytotoxic agents. When the 6-acetoamido-7-chloroquinoline-5,8-dione was reacted with alkylamines ( e.g. methylamine, ethylamine, propylamine, butylamine, β-chloroethylamine, benzylamine, β-hydroxyethylamine, and isopropylamine) 1-alkyl-2-methyl-imidazo[4,5-g]quinoline-4,9-dione(Ia-h) derivatives were obtained. And reaction with arylamines (e.g. aniline, 4-nitroaniline, 4-bromoaniline, 4-ethoxyaniline, 4-chloroaniline, 4-methylniline, and 4-trifluoro-methylaniline) gave 1-aryl-2-methyl-imidazo[4,5-g]quinoline-4,9-dione(IIa-g) derivatives. Reaction of 6,7-dichloroquinoline-5,8-dione(1) with piperidine, morpholine and thiomorpholine resulted in a four ring-closed compounds like 1,2,3,4-tetrahydropyrido[1,2-a]imidazo[4,5-g]quinoline-6,11-dione(IIIa), morpholino[1,2-a]imidazo[4,5-g]quinoline-6,11-dione(IIIb), thiomorpholino[1,2-a]imidaz[4,5-g]quinoline-6,11-dione(IIIc). Cytotoxicities of synthesized compounds were tested in SRB (SulfoRhodamin B) assay through the cell lines of A549 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), XF 498 (human CNS), and HCT 15 (human colon). Four ring-closed imidazoquino-linedione derivaives showed higher than three ring-closed compounds. To study their anticancer effects theoretically, we calculated the DNA-Interacion energies(ΔΕ) and the logP values but they showed no relationship to cytotoxicity.