Velders Aldrik H, Bergamo Alberta, Alessio Enzo, Zangrando Ennio, Haasnoot Jaap G, Casarsa Claudia, Cocchietto Moreno, Zorzet Sonia, Sava Gianni
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
J Med Chem. 2004 Feb 26;47(5):1110-21. doi: 10.1021/jm030984d.
Ruthenium compounds have gained large interest for their potential application as chemotherapeutic agents, and in particular the complexes of the type (X)[trans-RuCl4(dmso-S)L] (X = HL or Na, NAMI-A or NAMI, respectively, for L = imidazole) are under investigation for their antimetastatic properties. The NAMI(-A)-like compounds are prodrugs that hydrolyze in vivo, and the investigation of their hydrolytic properties is therefore important for determining the nature of the potential active species. The NAMI-A-type Ru(III) complex 1, (Hdmtp)[trans-RuCl4(dmso-S)(dmtp)] (dmtp is 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine), and the corresponding sodium analogue 2, (Na)[trans-RuCl4(dmso-S)(dmtp)], were synthesized. The hydrolyses of 1 and 2 in water as well as in buffered solutions were studied, and the first hydrolysis product, [mer-RuCl3(H2O)(dmso-S)(dmtp)].H2O (3), was isolated and characterized. The molecular structures of 1 and 3 were determined by single-crystal X-ray diffraction analyses and prove the importance of the hydrogen-bonding properties of dmtp to stabilize hydrolysis products. In vitro 1 (a) is not cytotoxic on tumor cells, following challenges from 1 to 72 h and concentrations up to 100 microM, (b) inhibits matrigel invasion at 0.1 mM and MMP-9 activity with an IC50 of about 1 mM, and (c) is devoid of pronounced effects on cell distribution among cell cycle phases. In vivo compound 1, similar to NAMI-A, significantly inhibits metastasis growth in mice bearing advanced MCa mammary carcinoma tumors. In the lungs, 1 is significantly less concentrated than NAMI-A, whereas no differences between these two compounds were found in other organs such as tumor, liver, and kidney. However, 1 caused edema and necrotic areas on liver parenchyma that are more pronounced than those caused by NAMI-A. Conversely, glomerular and tubular changes on kidney are less extensive than with NAMI-A. In conclusion, 1 confirms the excellent antimetastatic properties of this class of NAMI-A-type compounds and qualifies as an interesting alternative to NAMI-A for treating human cancers.
钌化合物因其作为化疗药物的潜在应用而备受关注，特别是(X)[反式-RuCl4(dmso-S)L]类型的配合物（对于L = 咪唑，X分别为HL或Na、NAMI-A或NAMI）正在因其抗转移特性而接受研究。类NAMI(-A)化合物是在体内水解的前药，因此研究它们的水解特性对于确定潜在活性物种的性质很重要。合成了NAMI-A型Ru(III)配合物1，(Hdmtp)[反式-RuCl4(dmso-S)(dmtp)]（dmtp是5,7-二甲基[1,2,4]三唑并[1,5-a]嘧啶），以及相应的钠类似物2，(Na)[反式-RuCl4(dmso-S)(dmtp)]。研究了1和2在水以及缓冲溶液中的水解情况，并分离和表征了第一个水解产物[mer-RuCl3(H2O)(dmso-S)(dmtp)].H2O (3)。通过单晶X射线衍射分析确定了1和3的分子结构，证明了dmtp的氢键性质对稳定水解产物的重要性。在体外，(a)在1至72小时的挑战以及高达100 microM的浓度下，1对肿瘤细胞无细胞毒性，(b)在0.1 mM时抑制基质胶侵袭，对MMP-9活性的IC50约为1 mM，并且(c)对细胞周期各阶段的细胞分布没有明显影响。在体内，化合物1与NAMI-A类似，能显著抑制患有晚期MCa乳腺癌肿瘤的小鼠的转移生长。在肺部，1的浓度明显低于NAMI-A，而在其他器官如肿瘤、肝脏和肾脏中未发现这两种化合物之间的差异。然而，1导致肝实质出现水肿和坏死区域，比NAMI-A引起的更明显。相反，肾脏的肾小球和肾小管变化比NAMI-A引起的范围更小。总之，1证实了这类NAMI-A型化合物具有优异的抗转移特性，有资格作为治疗人类癌症的NAMI-A的有趣替代物。
