N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors,ChemMedChem

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N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-05 , DOI: 10.1002/cmdc.202000762
Marco Mottinelli _{1,

2} , Maša Sinreih ₃ , Tea L Rižner ₃ , Mathew P Leese ₁ , Barry V L Potter _{1,

4}

Affiliation

17β‐Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less‐active estrone to estradiol, and inhibitors have therapeutic potential in estrogen‐dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N‐phenyl‐1,2,3,4‐tetrahydroisoquinoline (THIQ) template was pursued by using Pomeranz‐Fritsch‐Bobbitt, Pictet‐Spengler and Bischler‐Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure‐activity relationships are discussed. THIQs possessing a 6‐hydroxy group, lipophilic substitutions at the 1‐ or 4‐positions in combination with N‐4′‐chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC₅₀ of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.

中文翻译：

N-Phenyl-1,2,3,4-四氢异喹啉：设计 17β-羟基类固醇脱氢酶 1 抑制剂的替代支架

17β-羟基类固醇脱氢酶催化氧化和还原形式的甾体核受体配体之间 C17 位的相互转化。在恶性细胞中表达的 1 型酶催化活性较低的雌酮还原为雌二醇，抑制剂在雌激素依赖性疾病（如乳腺癌和卵巢癌）以及子宫内膜异位症中具有治疗潜力。非甾体N的合成装饰通过使用 Pomeranz-Fritsch-Bobbitt、Pictet-Spengler 和 Bischler-Napieralski 方法来探索-苯基-1,2,3,4-四氢异喹啉（THIQ）模板，以探索该支架作为类固醇模拟物的可行性。作为重组蛋白来源的细菌细胞匀浆中的 1 型酶抑制剂，在体外对衍生物进行了生物学评估。讨论了构效关系。具有 6-羟基、1-或 4-位亲脂取代与N -4'-氯苯基取代相结合的THIQ 最有利于活性。其中，一种化合物的 IC ₅₀约为₅₀倍。350 nM 作为外消旋体，证明了这种新方法的适用性。

更新日期：2021-01-10

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