Uehling D E, Nanthakumar S S, Croom D, Emerson D L, Leitner P P, Luzzio M J, McIntyre G, Morton B, Profeta S, Sisco J
Department of Medicinal Chemistry, Glaxo Inc., Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1995 Mar 31;38(7):1106-18. doi: 10.1021/jm00007a008.
A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7. Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay. Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide. Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay. These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts. The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls. Finally, 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7. Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility. A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts. The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.
通过全合成获得了一系列基于新型模板11-氮杂-(20S)-喜树碱的类似物，并在拓扑异构酶I酶可裂解复合物测定中作为潜在的抗癌药物进行了测试。母体化合物11-氮杂-(20S)-喜树碱(8)由已知的氨基吡啶衍生物3-(3-氨基-4-吡啶基亚甲基)-对甲苯胺与光学活性三环酮7经Friedländer缩合反应制得。在小牛胸腺拓扑异构酶I可裂解复合物测定中，化合物8的活性约为(20S)-喜树碱的两倍。制备了其中11-氮杂氮原子被季铵化为相应的N-氧化物或甲基碘的化合物。N-11季铵化的化合物显示出改善的水溶性，并且在可裂解复合物测定中与临床研究的喜树碱类似物拓扑替康具有同等效力。在携带HT-29人结肠癌异种移植瘤的裸鼠中对这些化合物进行了体内评价。与未处理的对照相比，发现类似物11-氮杂-(20S)-喜树碱11-N-氧化物显著延缓肿瘤生长。最后，使用10-溴-7-烷基-11-氮杂-(20S)-喜树碱19和20的Pd(0)偶联反应合成了7,10-二取代的11-氮杂喜树碱类似物，而19和20又可由新型溴吡啶衍生物17a和17b与7经Friedländer缩合反应制得。在10-取代系列中，许多类似物对拓扑异构酶I显示出极高的体外效力并改善了水溶性。发现大量化合物在全细胞细胞毒性测定中具有活性，并且有几种在携带HT-29肿瘤异种移植瘤的裸鼠中进行了评价。其中最有效的是(S)-11-氮杂-7-乙基-10-(氨基羟肟基甲基)喜树碱三氟乙酸盐(27)，一种有效的拓扑异构酶I抑制剂，在短期和长期体内试验中均显示出优异的疗效。该系列中其他化合物的体外酶数据与裸鼠研究的体内数据之间的比较表明，体外拓扑异构酶抑制与体内抗肿瘤疗效之间的总体相关性较差。
