Design, synthesis, and biological evaluation of analogues of the antitumor agent, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469)
Design, synthesis, and biological evaluation of analogues of the antitumor agent, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469)
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DOI：
10.1021/jm0005149
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发表时间：
2001-05-24
影响因子：
7.3
通讯作者：
Horwitz, JP
中科院分区：
文献类型：
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作者：
Hazeldine, ST;Polin, L;Horwitz, JP
2-{4-[（7-氯-2-喹啉基）氧]苯氧基丙酸（XK469）是我们实验室评估过的最具高度和广泛活性的抗肿瘤药物之一，目前计划于2001年进入临床试验。XK469的作用机制还有待进一步研究。因此，通过对XK469类似物的合成和对结构修饰对实体肿瘤活性的影响的评估，研究人员开始努力建立药效团假说，以描述活性位点的要求。所制定的策略选择将二维亲本结构分解为三个区域：i，喹诺啉A环；二、对苯二酚连接件联动；第三，乳酸浓度，以确定每个区域的化学变化在体外和体内产生的影响。XK469未取代的a环和b环3-氯区域异构体均未显示抗肿瘤活性。不同电负性取代基的调节抗肿瘤作用(s)，位于几个位置，包括区a环的I，然后确定。因此，位于2-{4-[（2-喹啉基）氧]苯氧基丙酸7位的卤素取代基产生了最具高度和广泛活性的抗肿瘤药物。甲基、甲氧基或叠氮取代基在该位置产生的活性结构要低得多，而5-、6-、8-氯、6-、7-硝基和7-氨基衍生物都被证明基本上是无活性的。当1的连接键（II区）从对苯二酚变为间苯二酚或儿茶酚衍生物时，所有的抗肿瘤活性都丧失了。在XK469 （III区）的羧酸衍生物，即CONH2、CONHCH3、CON(CH3)2、CONHOH、CONHNH2、CN或CN4H（四唑）中，只有单甲基和n， n -二甲酰胺被证明是有活性的。
2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories and is currently scheduled to enter clinical trials in 2001. The mechanism or mechanisms of action of XK469 remain to be elaborated. Accordingly, an effort was initiated to establish a pharmacophore hypothesis to delineate the requirements of the active site, via a comprehensive program of synthesis of analogues of XK469 and evaluation of the effects of structural modification(s) on solid tumor activity. The strategy formulated chose to dissect the two-dimensional parent structure into three regionsI, ring A of quinoxaline; II, the hydroquinone connector linkage; and III, the lactic acid moietyto determine the resultant in vitro and in vivo effects of chemical alterations in each region. Neither the A-ring unsubstituted nor the B-ring 3-chloro-regioisomer of XK469 showed antitumor activity. The modulating antitumor effect(s) of substituents of differing electronegativities, located at the several sites comprising the A-ring of region I, were next ascertained. Thus, a halogen substituent, located at the 7-position of a 2-{4-[(2-quinoxalinyl)oxy]phenoxy}propionic acid, generated the most highly and broadly active antitumor agents. A methyl, methoxy, or an azido substituent at this site generated a much less active structure, whereas 5-, 6-, 8-chloro-, 6-, 7-nitro, and 7-amino derivatives all proved to be essentially inactive. When the connector linkage (region II) of1was changed from that of a hydroquinone to either a resorcinol or a catechol derivative, all antitumor activity was lost. Of the carboxylic acid derivatives of XK469 (region III), i.e., CONH2, CONHCH3, CON(CH3)2, CONHOH, CONHNH2, CN, or CN4H (tetrazole), only the monomethyl- andN,N-dimethylamides proved to be active.