A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase.
A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase.
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一类新型非甾体芳香酶抑制剂：色酮和呫吨酮衍生物的设计和合成以及 P450 酶芳香酶和 17 α-羟化酶/C17,20-裂解酶的抑制。
DOI：
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发表时间：
2001
影响因子：
7.3
通讯作者：
R. Hartmann
中科院分区：
文献类型：
--
作者：
M. Recanatini;A. Bisi;A. Cavalli;F. Belluti;S. Gobbi;A. Rampa;P. Valenti;Martina Palzer;and Anja Palusczak;R. Hartmann
芳香化酶（P450 arom）是治疗乳腺癌的药理学目标。在本文中，我们报告了一系列新的（二）苯并吡喃酮为基础的抑制剂的设计，合成和体外生物学评价。新化合物的设计是由先前开发的一系列非甾体芳香酶抑制剂的CoMFA模型指导的。色酮和氧杂蒽酮核都被视为分子骨架，其功能被认为是结合芳香酶活性位点--杂环的关键（咪唑或1，3，4-三唑）通过亚甲基单元和H-键接受官能团连接到芳族部分（CN，NO（2），Br）位于芳环上，与携带孤对电子的杂环氮原子相距适当距离。通过常规的合成方法，从适当的甲基类似物制备色酮、氧杂蒽酮和黄酮衍生物。采用Thompson和Siiteri的方法，用人胎盘微粒体和[1 β，2 β-（3）H]睾酮作为标记底物，测定芳香酶抑制活性。所有的化合物还测试了17 α-羟化酶/C17，20-裂解酶（P450 17），一种酶的治疗前列腺疾病的治疗利益。用氧杂蒽酮衍生物22 d、e（IC（50）值分别为43和40 nM）实现了寻找新的有效芳香酶抑制剂的目标，其超过了已知参比药物法倔唑的效力，并且还显示出对P450 17的高选择性。此外，基于相同的黄酮核的化合物22 g-i显示出作为P450 17抑制剂的相当高的效力（IC（50）值分别为220、130和42 nM）。因此，它们可能是开发雄激素依赖性疾病候选药物的新线索。
Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site - a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO(2), Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair--were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1 beta,2 beta-(3)H]testosterone as the labeled substrate. All the compounds were also tested on 17 alpha-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC(50) values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g-i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC(50) values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.