Hoffmann Kamil, Wiśniewska Joanna, Wojtczak Andrzej, Sitkowski Jerzy, Denslow Agnieszka, Wietrzyk Joanna, Jakubowski Mateusz, Łakomska Iwona
Bioinorganic Chemistry Research Group, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, Gagarina 7, 87-100 Toruń, Poland.
Faculty of Chemistry, Nicolaus Copernicus University in Toruń, Gagarina 7, 87-100 Toruń, Poland.
J Inorg Biochem. 2017 Jul;172:34-45. doi: 10.1016/j.jinorgbio.2017.04.003. Epub 2017 Apr 4.
Six novel platinum(II) complexes containing purine-mimetic ligands (5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp)) and dicarboxylato ligands (glutarato (glut) or cyclobutane-1,1-dicarboxylato (CBDC)) have been prepared and characterized with multinuclear magnetic resonance (H, C, N, Pt) NMR, infrared (IR) and X-ray crystallography. Spectroscopic data in solid state and in solution unambiguously confirm the square-planar geometry of Pt(II) with two monodentate N3-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine ligands and one O-chelating dicarboxylato ligand. Next, the effect of all the platinum(II) compounds on the viability of normal or cancer cells and their putative mechanisms of action have been investigated. Of the studied platinum(II) complexes, two ([Pt(glut)(dbtp)] and [Pt(CBDC)(dbtp)]) overcame the cisplatin resistance in human ovarian tumor cells (A2780cis or OVCAR-3) and arrested the cell cycle at S phase in mice mammary gland cancer cells (4T1), which indicates a mechanism of action different from that of cisplatin. Interestingly, preliminary in vivo toxicity assays revealed that both compounds tested in mice ([Pt(glut)(dbtp)] 3 and [Pt(CBDC)(dbtp)] 6) were less toxic in vivo than cisplatin or oxaliplatin. Additionally, compound 6 did not cause myelosuppression and showed over fivefold less accumulation in the liver than its glutarato analog 3.
制备了六种含有嘌呤模拟配体（5,7 - 二甲基 - 1,2,4 - 三唑并[1,5 - a]嘧啶（dmtp）、7 - 异丁基 - 5 - 甲基 - 1,2,4 - 三唑并[1,5 - a]嘧啶（ibmtp）、5,7 - 二叔丁基 - 1,2,4 - 三唑并[1,5 - a]嘧啶（dbtp））和二羧酸配体（戊二酸（glut）或环丁烷 - 1,1 - 二羧酸（CBDC））的新型铂（II）配合物，并通过多核磁共振（H、C、N、Pt）NMR、红外（IR）和X射线晶体学对其进行了表征。固态和溶液中的光谱数据明确证实了铂（II）的平面正方形几何结构，其具有两个单齿N3键合的5,7 - 二取代 - 1,2,4 - 三唑并[1,5 - a]嘧啶配体和一个O - 螯合二羧酸配体。接下来，研究了所有铂（II）化合物对正常细胞或癌细胞活力的影响及其假定的作用机制。在所研究的铂（II）配合物中，两种（[Pt（glut）（dbtp）]和[Pt（CBDC）（dbtp）]）克服了人卵巢肿瘤细胞（A2780cis或OVCAR - 3）中的顺铂耐药性，并使小鼠乳腺癌细胞（4T1）的细胞周期停滞在S期，这表明其作用机制与顺铂不同。有趣的是，初步的体内毒性试验表明，在小鼠中测试的两种化合物（[Pt（glut）（dbtp）] 3和[Pt（CBDC）（dbtp）] 6）在体内的毒性均低于顺铂或奥沙利铂。此外，化合物6不会引起骨髓抑制，并且在肝脏中的蓄积量比其戊二酸类似物3少五倍以上。
