Vignaroli Giulia, Zamperini Claudio, Dreassi Elena, Radi Marco, Angelucci Adriano, Sanità Patrizia, Crespan Emmanuele, Kissova Miroslava, Maga Giovanni, Schenone Silvia, Musumeci Francesca, Botta Maurizio
Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy ; Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle Scienze 27/A, 43124 Parma, Italy.
ACS Med Chem Lett. 2013 May 20;4(7):622-6. doi: 10.1021/ml4000782. eCollection 2013 Jul 11.
Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (1 and 2), which led to the development of the corresponding and highly water-soluble antitumor prodrugs (7 and 8). In vitro studies confirmed a significant improvement of aqueous solubility and, for compound 8, good plasma stability, suggesting superior in vivo bioavailability. As expected, the uncleaved water-soluble prodrugs 7 and 8 showed no activity toward the enzymatic targets (c-Src and c-Abl) but revealed promising antiproliferative activity in myeloid cell lines, as a consequence of the in vitro hydrolysis of the selected solubilizing moiety, followed by the release of the active compounds (1 and 2).
设计和合成有前景的候选药物的前药是克服药物缺乏良好的吸收、分布、代谢和排泄（ADME）特性，特别是水溶性和生物利用度不足的有效策略。我们在此报告该策略在两种代表性吡唑并[3,4-d]嘧啶衍生物（1和2）上的成功应用，这导致了相应的高水溶性抗肿瘤前药（7和8）的开发。体外研究证实水溶性有显著提高，并且对于化合物8而言，具有良好的血浆稳定性，表明其体内生物利用度更高。正如预期的那样，未裂解的水溶性前药7和8对酶靶点（c-Src和c-Abl）无活性，但由于所选增溶部分的体外水解，随后释放出活性化合物（1和2），因而在髓系细胞系中显示出有前景的抗增殖活性。
