This work presents a deeper pharmacological evaluation of two formerly prepared and characterized, and highly in vitro cytotoxic platinum(II) oxalato complexes [Pt(ox)(L₁)₂] (1) and [Pt(ox)(L₂)₂] (2), containing the derivatives of cyclin-dependent kinase inhibitor (CDKi) seliciclib ((R)-roscovitine, CYC202) coordinating as N-donor carrier ligands, i.e., 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (L₁) and 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine (L₂). The positive results of in vitro cytotoxicity screening on human cancer cell lines (HeLa, HOS, A2780, A2780R, G361 and MCF7 with IC₅₀ at low micromolar levels) published previously, motivated us to perform extended preclinical in vitro experiments to reveal the mechanisms associated with the induction of cancer cell death. In addition, the in vivo antitumor activity was evaluated using the mouse lymphocytic leukaemia L1210 model. The obtained results revealed that complex 1 exceeds the antitumor effect of cisplatin (as for the extension of life-span of mice) and shows far less adverse effects as compared to reference drug cisplatin. The in vitro and ex vivo studies of cellular effects and molecular mechanisms of cell death induction showed that the mechanism of action of complex 1 is essentially different from that of cisplatin. The obtained results showed a possible way how to obtain antitumor active platinum(II) oxalato complexes with better therapeutic profile than contemporary used platinum-based therapeutics.

中文翻译：

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seliciclib（CYC202）衍生物的铂（II）-草酸酯复合物在小鼠淋巴瘤模型中显示出比顺铂不同的细胞作用，且不良反应较小

这项工作提出了对两种先前制备和表征的，具有高体外细胞毒性的草酸铂（II）草酸酯复合物[Pt（ox）（L ₁）₂ ]（1）和[Pt（ox）（L ₂）₂的更深入的药理评价。]（2），其包含作为N-供体载体配体配位的细胞周期蛋白依赖性激酶抑制剂（CDKi）seliciclib（（R）-roscovitine，CYC202）的衍生物，即2-（1-乙基-2-羟基乙基氨基）-N 6-（4-甲氧基苄基）-9-异丙基腺嘌呤（L ₁）和2-氯-N 6-（2,4-二甲氧基苄基）-9-异丙基腺嘌呤（L ₂）。先前发表的对人类癌细胞系（HeLa，HOS，A2780，A2780R，G361和MCF7 （低微摩尔水平）的IC ₅₀）进行体外细胞毒性筛选的积极结果促使我们开展扩展的临床前体外实验，以揭示相关机制诱导癌细胞死亡。另外，使用小鼠淋巴细胞白血病L1210模型评估了体内抗肿瘤活性。所获得的结果表明，复合物1超过了顺铂的抗肿瘤作用（就小鼠的寿命而言），并且与参考药物顺铂相比，其不良作用要小得多。对细胞作用和细胞死亡诱导分子机制的体外和离体研究表明，复合物的作用机制1与顺铂基本上不同。获得的结果显示了一种可能的方法，该方法可以获得比当代使用的基于铂的治疗剂更好的治疗特性的抗肿瘤活性草酸铂（II）配合物。