Moron J, Rautureau M, Huel C, Pierré A, Berthier L K, Atassi G, Bisagni E
URA 1387 CNRS, Laboratoire de Synthèse Organique, Orsay, France.
Anticancer Drug Des. 1993 Dec;8(6):399-416.
2-Acetyl-4-chloro-3-lithiopyridine ethylene glycol ketal (6b) was reacted with 3-formyl-5-methoxy-1-methyl-indole (9) and 3-formyl-1-methyl-1H-pyrrolo [3,2-c] pyridine (12), giving the corresponding expected alcohols. Reduction of these intermediates with triethylsilane trifluoroacetic acid and subsequent cyclodehydration then led to 4-chloro-7-methoxy-10,11-dimethyl-10H-pyrido [2,3-b] carbazole (8a) and the corresponding 7-aza-analog (8b). The synthesis of 4-chloro-11-methyl (and 5,11-dimethyl)-10-unsubstituted derivatives of these two series was performed through an independent pathway, involving condensation of conveniently substituted 2-amino carbazoles (17) and 7-amino-5H-pyrido [4,3-b] indoles (18) with 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, thermal cyclization of the resulting compounds with concomitant decarboxylation to the corresponding tetracyclic fused-4-quinolone systems and final chlorination with phosphorus oxychloride. Nucleophilic substitution of various 4-chloro derivatives was then easily performed in an excess of the required dialkylamino alkylamines at reflux and 4-amino substituted-7-hydroxy-10H- pyrido [2,3-b] carbazoles (25d-e) were obtained from 7-methoxy precursors (25a-b), by demethylation with boron tribromide in methylene chloride at -65 degrees C or with boiling 47% hydrobromic acid. Cytotoxicity determination of all new aminosubstituted derivatives and in vivo antitumor evaluation of the most active compounds clearly show that these two series of ellipticine analogs closely related to highly active products are devoid of antitumor properties in two experimental models shown to be sensitive to ellipticines. The place of the pyridinic nitrogen atom in these series has thus been demonstrated to play a crucial role in antitumor activity.
2-乙酰基-4-氯-3-锂代吡啶乙二醇缩酮（6b）与3-甲酰基-5-甲氧基-1-甲基吲哚（9）和3-甲酰基-1-甲基-1H-吡咯并[3,2-c]吡啶（12）反应，得到相应的预期醇类。用三乙基硅烷三氟乙酸还原这些中间体，随后进行环脱水反应，得到4-氯-7-甲氧基-10,11-二甲基-10H-吡啶并[2,3-b]咔唑（8a）和相应的7-氮杂类似物（8b）。这两个系列的4-氯-11-甲基（以及5,11-二甲基）-10-未取代衍生物的合成是通过一条独立的途径进行的，该途径包括将适当取代的2-氨基咔唑（17）和7-氨基-5H-吡啶并[4,3-b]吲哚（18）与5-（乙氧基亚甲基）-2,2-二甲基-1,3-二氧六环-4,6-二酮缩合，将所得化合物进行热环化并伴随脱羧反应生成相应的四环稠合-4-喹诺酮体系，最后用三氯氧磷进行氯化反应。然后，在过量的所需二烷基氨基烷基胺存在下，于回流条件下很容易进行各种4-氯衍生物的亲核取代反应，并且通过在-65℃的二氯甲烷中用三溴化硼脱甲基或用沸腾的47%氢溴酸处理，从7-甲氧基前体（25a-b）获得4-氨基取代的-7-羟基-10H-吡啶并[2,3-b]咔唑（25d-e）。所有新的氨基取代衍生物的细胞毒性测定以及最具活性化合物的体内抗肿瘤评估清楚地表明，这两个与高活性产物密切相关的椭圆玫瑰树碱类似物系列在两个对椭圆玫瑰树碱敏感的实验模型中均无抗肿瘤特性。因此，已证明这些系列中吡啶氮原子的位置在抗肿瘤活性中起关键作用。
