Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.
Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
Int J Mol Sci. 2022 Jun 25;23(13):7081. doi: 10.3390/ijms23137081.
Kiteplatin, [PtCl(-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand -1,2-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, ,,-[PtCl(OBz)(-1,4-DACH)] (; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to 60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·10 LLC cells implanted into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (75%) was observed by administering compound by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of was evaluated using an in vitro assay.
Kiteplatin，[PtCl(-1,4-DACH)]（DACH = 二氨基环己烷），含有奥沙利铂二胺配体的一种异构体 -1,2-DACH，并已被提议作为一种有价值的药物候选物，用于治疗顺铂和奥沙利铂耐药的肿瘤，特别是结直肠癌。为了进一步提高 kiteplatin 的活性，通过在轴向位置添加两个苯甲酸盐基团，将其转化为 Pt(IV)前药。新化合物，，，-[PtCl(OBz)(-1,4-DACH)]（；OBz = 苯甲酸盐），在纳摩尔浓度下对广泛的人类癌细胞系表现出细胞毒性活性。基于这些非常有前途的结果，研究已经扩展到化合物在 Lewis Lung Carcinoma (LLC) 模型中的体内活性及其口服给药的适用性。化合物在酸性条件下（pH 1.5 模拟胃环境）非常稳定，在 37°C 孵育 72 小时后，初始浓度仅下降到初始浓度的60%；因此适合口服给药。有趣的是，在小鼠模型（2·10 LLC 细胞植入 8 周龄雄性和雌性 C57BL 小鼠的右后腿）中，通过口服灌胃给予化合物和标准药物顺铂腹腔注射，观察到肿瘤质量的类似减少（75%），这表明kiteplatin 的这种双苯甲酸盐前药确实有可能口服给药。此外，由于 Pt(IV)前药的作用机制涉及通过化学还原初始激活为细胞毒性 Pt(II)物种，因此研究了两种生物还原剂（抗坏血酸/抗坏血酸钠和谷胱甘肽）还原的情况，结果表明还原相当缓慢（在 37°C 孵育 120 小时后仍未完全还原）。最后，使用体外测定评估了化合物的神经毒性。
