Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model,Journal of Medicinal Chemistry

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Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00637
Giulia Vignaroli _{1,

2} , Giulia Iovenitti _{1,

2} , Claudio Zamperini _{1,

2} , Federica Coniglio _{1,

2} , Pierpaolo Calandro ₁ , Alessio Molinari ₁ , Anna Lucia Fallacara ₁ , Andrea Sartucci ₁ , Alessia Calgani ₃ , David Colecchia ₄ , Andrea Mancini ₃ , Claudio Festuccia ₃ , Elena Dreassi ₁ , Massimo Valoti ₅ , Francesca Musumeci ₆ , Mario Chiariello ₄ , Adriano Angelucci ₃ , Maurizio Botta _{1,

2,

7} , Silvia Schenone ₄

Affiliation

Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4–4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.

中文翻译：

吡唑并[3,4- d ]嘧啶的前药：从文库合成到原位成胶质母细胞瘤模型中潜在抗癌药的评价

吡唑并[3,4- d ]嘧啶是有效的蛋白激酶抑制剂，具有有希望的抗肿瘤活性，但水溶性较差，因此值得进一步优化。在这里，我们提出了一锅两步程序，用于合成一组具有较高水溶性和增强的药代动力学和治疗特性的吡唑并[3,4- d ]嘧啶前药（1a - 8a和9a - e）。ADME研究表明，最有前途的前药具有更好的水溶性，在人和鼠血清中具有良好的水解作用，并且相对于母体药物而言，其跨细胞膜的能力增强，这说明了它们在体外24小时的性能更好对人胶质母细胞瘤U87细胞系的细胞毒性。最后，还对体内的4–4a药物/前药进行了评估，揭示了前药具有良好疗效的有利的药代动力学特征。事实证明，前药方法的应用是提高母体药物水溶性的成功策略，对它们的生物学功效也产生了积极影响。

更新日期：2017-07-19

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