2-cyclopropylindoloquinones and their analogues as bioreductively activated antitumor agents: Structure-activity in vitro and efficacy in vivo
2-cyclopropylindoloquinones and their analogues as bioreductively activated antitumor agents: Structure-activity in vitro and efficacy in vivo
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DOI：
10.1021/jm9608422
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发表时间：
1997-07-18
影响因子：
7.3
通讯作者：
Stratford, IJ
中科院分区：
文献类型：
--
作者：
Naylor, MA;Jaffar, M;Stratford, IJ
合成了一系列2-环烷基和2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones及其对应的氨基甲酸酯类化合物，并在5-位与各种取代和未取代的氮杂环丙烷进行了取代反应。体外对低氧细胞的细胞毒性依赖于3-羟甲基类似物的5-氮丙基或取代氮杂环丁基的存在。5-甲氧基的活性依赖于3-(氨基甲酰氧基)甲基取代基的存在。增加2-位的空间体积会降低化合物对低氧细胞的有效性。2-环丙基取代基比2-异丙基取代基的效率高2个数量级，这表明可能的自由基开环反应对毒性有贡献。非稠合的2-环丙基丝裂原烯类药物比相关的稠环丙基亚胺类化合物更有效。对苯二酚/半对苯二酚单电子对的还原电位范围为-286~-380 mV。半醌自由基与氧的反应速率常数为2-8×10(8)dm(3)摩尔(-1)S(-1)。两电子还原对苯二酚参与了细胞毒性的调节。体外最有效的化合物是2-环丙基和5-(2-甲基氮丙基)衍生物，其中5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxylindole)-1-methylindole-4，7-dione(21)和3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1，2-dimethylindole-4，7-dione(54)进行了体内评价。这两种化合物都显示出作为单药和与放射联合使用的抗肿瘤活性，在最大耐受剂量和作为针对RIF-1肿瘤模型的单药以及在KHT肿瘤模型中的类似效果方面，都比EO9(3)有一些实质性的改善。
A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones and corresponding carbamates have been synthesized and substituted in the 5-position with a variety of substituted and unsubstituted aziridines. Cytotoxicity against hypoxic cells in vitro was dependent upon the presence of a 5-aziridinyl or a substituted aziridinyl substituent for 3-hydroxymethyl analogues. The activity of 5-methoxy derivatives was dependent upon the presence of a 3-(carbamayloxy)methyl substituent. Increasing the steric bulk at the 2-position reduced the compounds' effectiveness against hypoxic cells. A 2-cyclopropyl substituent was up to 2 orders of magnitude more effective than a 2-isopropyl substituent, suggesting possible radical ring-opening reactions contributing to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduction potentials of the quinone/semiquinone one-electron couples were in the range -286 to -380 mV. The semiquinone radicals reacted with oxygen with rate constants 2-8 x 10(8) dm(3) mol(-1) s(-1). The involvement of the two-electron reduced hydroquinone in the mediation of cytotoxicity is Implicated. The most effective compounds in vitro were the 2-cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, 5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxylindole)-1-methylindole-4,7-dione (21) and 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1,2-dimethylindole-4,7-dione (54) were evaluated in vivo. Both compounds showed antitumor activity both as single agents and in combination with radiation, with some substantial improvements over EO9 (3) at maximum tolerated doses and as single agents against the RIF-1 tumor model and comparable efficacy in the KHT tumor model.