17-(2'-噁唑基)-雄甾体衍生物的合成及其抑制17α-羟化酶/C17,20-裂解酶的活性

17-(2'-噁唑基)-雄甾体衍生物的合成及其抑制17α-羟化酶/C_17,20-裂解酶的活性

朱娜, 赵娜, 雷小平, 凌仰之^*, VenkatechHundratta, AngelaBrodie

1.北京大学药学院药物化学系, 北京 100082;
2.美国马里兰大学医学院, 巴尔的摩, Maryland 21201

收稿日期:2000-08-19 修回日期:2001-01-08 出版日期:2001-03-15 发布日期:2001-03-15
通讯作者: 凌仰之*

The Synthesis of Some 17-(2'-Oxazolyl)-androsta-5,16-diene Derivatives as 17α-Hydroxylase/C_17,20-Lyase Inhibitors

Zhu Na, Zhao Na, Lei Xiaoping, Ling Yangzhi^*, Venkatech Hundratta, Angela Brodie

1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing 100082
2. Department of Pharmacology & Experimental Therapeutics, School of Medicine, University of Maryland. Baltimore, Maryland 21201

Received:2000-08-19 Revised:2001-01-08 Online:2001-03-15 Published:2001-03-15
Contact: Ling Yangzhi*

摘要/Abstract

摘要：

设计和合成了一些4'-和5'-取代的17-(2'-噁唑基)-雄甾-5,16-二烯衍生物作为_17α-羟化酶/C17,20-裂解酶(P45017α) 的抑制剂,用以治疗前列腺癌。药理筛选结果表明,化合物6c,即17-(2'-噁唑基)-雄甾-5,16-二烯-3-醇为强的抑制剂,其活性可与欲进入临床I 期的标准对VN85相当。在噁唑基4' 或5'位上甲基或苯基基团的引入降低了生物活性。如预期所料,其3-醋酸酯5a～c和8的体外活性要弱于其相应的3-羟基物6a~c 和9。化合物6c 的深入药理实验在进行中。

关键词: 17-噁唑基雄甾烯, P450_17α抑制剂, 前列腺癌, 生物电子等排

Abstract:

Several 4'- and 5'-substituted 17-(2'-oxazolyl)-androsta-5,16-diene derivatives were designed and synthesized as inhibitors of 17α-hydroxylase/C17,20-Lyase (P45017α) for the treatment of prostatic cancer, the results of the preliminary pharmacological screening showed that compound 6c, i.e. 17-(2'-oxazoly)-androsta-5,16-diene-3-ol was a strong inhibitor, comparable with that of the reference compound VN-85. The introduction of methyl or phenyl group at the 4' or 5' position of oxazole ring decreased the activity. The in vitro activities of 3-acetate 5a~c and 8 were lower than their 3-ol counterparts 6a～c and 9 as expected. The further pharmacological study of 6c is in progress.

Key words: 17-Oxazolyl androstene, P450_17αInhibitors, Prostate cancer, Bioisosterism

Supporting:

^*This work was supported by the National Natural Science Foundation of China (No. 39670855) and NIH Grant CA 27740 of USA.

朱娜, 赵娜, 雷小平, 凌仰之^*, VenkatechHundratta, AngelaBrodie

. 17-(2'-噁唑基)-雄甾体衍生物的合成及其抑制17α-羟化酶/C_17,20-裂解酶的活性[J]. .

Zhu Na, Zhao Na, Lei Xiaoping, Ling Yangzhi^*, Venkatech Hundratta, Angela Brodie

. The Synthesis of Some 17-(2'-Oxazolyl)-androsta-5,16-diene Derivatives as 17α-Hydroxylase/C_17,20-Lyase Inhibitors[J]. .

[1]	洪艺华, 刘曈彤, 刘彦君, 吴竞轩, 杨晓改. 钒化合物通过活性氧水平的调节对PTEN表达缺失的前列腺癌细胞发挥更强的抑制作用[J]. 中国药学(英文版), 2017, 26(6): 432-439.
[2]	周代营, 丁立, 王希, 马娟, 黄沃林, Susan Goodin, 郑希. 姜黄素类似物和多西紫杉醇对人前列腺癌细胞生长的协同作用[J]. 中国药学(英文版), 2017, 26(11): 827-833.
[3]	茹呈杰, 雷小平, 凌仰之^*, 张礼和, VenkatechHundratta, AngelaBrodie. 17α -羟化酶/C_17,20-裂解酶(P450_17α )抑制剂-17-[(2' -取代的)-4' -嘧啶基]雄烯衍生物的合成及药理活性[J]. , 2001, 10(1): 3-8.