An unsymmetric cisplatin-based Pt(IV) derivative containing 2-(2-propynyl) octanoate: a very efficient multi-action antitumor prodrug candidate

Gabano Elisabetta; Ravera Mauro; Zanellato Ilaria; Tinello Stefano; Gallina Andrea; Rangone Beatrice; Gandin Valentina; Marzano Cristina; Bottone Maria Grazia; Osella Domenico

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An unsymmetric cisplatin-based Pt(IV) derivative containing 2-(2-propynyl) octanoate: a very efficient multi-action antitumor prodrug candidate

机译：含有2-（2-丙基）辛酸的非对称顺铂的PT（IV）衍生物：非常有效的多动作抗肿瘤前药候选者

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The design, synthesis, characterization and biological properties of a Pt(IV) complex containing the very active inhibitor of histone deacetylase (2-propynyl) octanoic acid, POA, as an axial ligand are reported here. The title complex, namely (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl) octanoato) platinum(IV), 1, containing POA in racemic or in enantiomeric forms, was one/two orders of magnitude more active than cisplatin, depending on the chemo-sensitivity of the cancer cell lines. Moreover, 1 exhibited similar or even better antiproliferative activity than (OC-6-33)-diamminedichloridobis(2-propylpentanoato) platinum(IV), 2, containing two molecules of the well-known histone deacetylase inhibitor 2-propylpentanoic (valproic) acid. The high potency of 1 is likely due to its high cellular accumulation and to the synergism between the DNA-damaging cisplatin and the histone deacetylase inhibitor POA, both released upon the intracellular reduction of 1. Prodrug 1, after oral administration, caused an impressive reduction of the tumor mass (94%) in a model of solid tumor (murine Lewis lung carcinoma), compared to that of the control, whereas (intraperitoneal) cisplatin induced a tumor regression of 75% only. A good accumulation of 1 was observed in the tumor mass. The time course of the body weight attested that cisplatin induced elevated anorexia, whereas treatment with 1 did not induce significant body weight loss throughout the therapeutic experiment.

机译：在此报道含有含有组蛋白脱乙酰化酶（2-丙炔基）辛酸，POA，作为轴向配体的非常活性抑制剂的Pt（iv）络合物的设计，合成，表征和生物学特性。标题复合物，即（OC-6-44） - 丙替其二胺二氯丙烷（2-（2-丙炔基）辛烷酯）铂（IV），1，含有外消旋或对映体形式的POA，是一个/两个数量级更活跃顺铂，取决于癌细胞系的化学敏感性。此外，1表现出与（OC-6-33） - 亚胺二氯胺（2-丙基戊烷）铂（IV），2，含有众所周知的组蛋白脱乙酰化酶抑制剂2-丙基戊烯（丙丙基）酸的两种分子（IV-6-33）相似或甚至更好的抗增殖活性。。要求1所述的高效力可能是由于它的高的细胞积累和DNA损伤性顺铂和组蛋白脱乙酰酶抑制剂POA，二者在细胞内减少1.前药1的释放之间的协同作用，口服给药后，引起令人印象深刻的还原与对照组相比，固体瘤模型（94％）的肿瘤质量（94％），而（腹膜内）仅诱导75％的肿瘤回归。在肿瘤质量中观察到良好的1。体重的时间过程证明了顺铂诱导的厌食升高，而1的处理在整个治疗实验中没有诱导显着的体重减轻。

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来源
《Dalton transactions: An international journal of inorganic chemistry》 |2017年第41期|共12页
作者
Gabano Elisabetta; Ravera Mauro; Zanellato Ilaria; Tinello Stefano; Gallina Andrea; Rangone Beatrice; Gandin Valentina; Marzano Cristina; Bottone Maria Grazia; Osella Domenico;
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作者单位

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

Univ Padua Dipartimento Sci Farmaco Via Marzolo 5 I-35131 Padua Italy;

Univ Padua Dipartimento Sci Farmaco Via Marzolo 5 I-35131 Padua Italy;

Univ Pavia Dipartimento Biol &

Biotecnol L Spallanzani Via Ferrata 9 I-27100 Pavia Italy;

Univ Piemonte Orientale Dipartimento Sci &

Innovaz Tecnol Viale Michel 11 I-15121 Alessandria Italy;

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中图分类化学;无机化学;
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机译：含有2-（2-丙基）辛酸的非对称顺铂的PT（IV）衍生物：非常有效的多动作抗肿瘤前药候选者
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An unsymmetric cisplatin-based Pt(IV) derivative containing 2-(2-propynyl) octanoate: a very efficient multi-action antitumor prodrug candidate

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