2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes.,Journal of Medicinal Chemistry

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2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-11 , DOI: 10.1021/acs.jmedchem.9b01611
Sanjay Bhattarai ₁ , Jan Pippel ₂ , Emma Scaletti ₂ , Riham Idris ₁ , Marianne Freundlieb ₁ , Georg Rolshoven ₁ , Christian Renn ₁ , Sang-Yong Lee ₁ , Aliaa Abdelrahman ₁ , Herbert Zimmermann ₃ , Ali El-Tayeb ₁ , Christa E Müller ₁ , Norbert Sträter ₂

Affiliation

CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5'-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.

中文翻译：

2位取代的α，β-亚甲基ADP衍生物：具有可变结合模式的强效竞争性Ecto-5'-核苷酸酶（CD73）抑制剂。

CD73抑制剂是用于癌症（免疫）治疗的有前途的药物。在这里，我们介绍了合成，结构-活性关系，和竞争性CD73抑制剂α，β-亚甲基-ADP（AOPCP）取代2位的新型衍生物的共晶体结构。小极性或亲脂性残基增加了效力，2-碘-和2-氯腺苷-5'-O-[（膦酰基甲基）膦酸]（15、16）是对人CD73的Ki值为3-的最有效抑制剂6 nM。取决于2-取代基的大小和性质，通过X射线晶体学观察到可变的结合模式。取决于结合模式，发现了较大的物种差异，例如，2-哌嗪基-AOPCP（21）与人CD73相比，对大鼠CD73的效力低> 12倍。这项研究表明，只需将一个小的取代基引入AOPCP的2位即可实现高CD73抑制力，而无需额外的大体积N6-取代基。此外，它为竞争性CD73抑制剂的结合模式提供了宝贵的见解，为药物开发提供了极好的基础。

更新日期：2020-03-02

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