Vignaroli Giulia, Iovenitti Giulia, Zamperini Claudio, Coniglio Federica, Calandro Pierpaolo, Molinari Alessio, Fallacara Anna Lucia, Sartucci Andrea, Calgani Alessia, Colecchia David, Mancini Andrea, Festuccia Claudio, Dreassi Elena, Valoti Massimo, Musumeci Francesca, Chiariello Mario, Angelucci Adriano, Botta Maurizio, Schenone Silvia
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
Lead Discovery Siena S.r.l. , via Vittorio Alfieri 31, Castelnuovo Berardenga, 53019 Siena, Italy.
J Med Chem. 2017 Jul 27;60(14):6305-6320. doi: 10.1021/acs.jmedchem.7b00637. Epub 2017 Jul 18.
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.
吡唑并[3,4 - d]嘧啶是具有良好抗肿瘤活性的强效蛋白激酶抑制剂，但水溶性欠佳，因此值得进一步优化。在此，我们展示了一种一锅两步法来合成一组具有更高水溶性以及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）。药物代谢动力学研究表明，对于最有前景的前药而言，相较于母体药物，它们具有更好的水溶性、在人和小鼠血清中更有利的水解作用以及更强的跨细胞膜能力，这解释了它们对人胶质母细胞瘤U87细胞系具有更好的24小时体外细胞毒性。最后，还对4 - 4a这对药物/前药进行了体内评估，结果显示前药具有有益的药代动力学特征且疗效良好。前药方法的应用被证明是提高母体药物水溶性的成功策略，对其生物学疗效也产生了积极影响。
