色胺酮衍生物设计、合成及抗肿瘤活性构效关系研究

Design, Synthesis and Structure-Activity Relationship of Tryptanthrins as Antitumor Agents

首先合成吲哚醌衍生4a^4f,氧化水解得到邻氨基苯甲酸衍生物5a^5d.以这两者为原料设计合成A和/或D环取代的色胺酮衍生物1a^1q.然后,以色胺酮6位酮羰基分别与水合肼、盐酸羟胺反应生成C环席夫碱结构.最后,以哌嗪结构取代B环嘧啶酮合成茚(1,2-b)喹喔啉-11-酮.共设计合成20个化合物,其中新化合物13个.对所合成化合物的结构经红外光谱、核磁氢谱、元素分析确证.测定所合成化合物对肿瘤细胞A549的体外抑制活性.结果表明化合物1b,1c,1i,1j,1p和1q表现出较强的肿瘤细胞抑制活性,IC50值分别为3.58,0.99,1.03,2.10,0.51和0.43μmol·L-1.构效关系研究表明:D环卤素取代提高抗肿瘤活性,而取代基团在A环时则减弱抗肿瘤活性;B环(嘧啶环)被哌嗪环取代后抗肿瘤活性消失(IC50>100μmol·L-1);而C环酮羰基生成席夫碱结构抗肿瘤活性与色胺酮相当.

The isatin derivatives 4a^4f were prepared and underwent oxidative hydrolysis to give the anthranilic acid 5a^5d. A and/or D-ring substituted tryptanthrins were designed and synthesized from 4a^4f to 5a^5d. Then C-ring Schiff bases of tryptanthrin were synthesized by condensation of 6-carbonyl with hydrazine and hydroxylamine hydrochloride. Finally, the B-ring was replaced with piperazine to give 11H-indeno[1,2-b]quinoxalin-11-one. 20 compounds were synthesized and their structures were confirmed by 1H NMR, IR and elemental analysis. To best of our knowledge, 13 of them were unknown in the literature. The antitumor activities of synthesized compounds were evaluated against A549 cell line in vitro. The preliminary results indicated that 1b, 1c, 1i, 1j, 1p and 1q showed good antitumor activity with the IC50 of 3.58, 0.99, 1.03, 2.10, 0.51 and 0.43 μmol·L-1, respectively. Structure-activity relationship showed that halogen substitution located in the D-ring enhanced the anti-tumor activity, while the same substitution located in the A ring reduced the activity. The anti-tumor activity disappeared when B-ring was replaced by piperazine, while there was no significant difference for tryptanthrin and its C-ring Schiff base.