Ruthenium(II) complexes (Ru1–Ru5), with the general formula [Ru(N-S)(dppe)₂]PF₆, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC₅₀ values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru(dmp)(dppe)₂]PF₆ (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1–Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests.

中文翻译：

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钌 (II) 二膦与巯基配体的复合物可抑制拓扑异构酶 IB 并抑制体内肿瘤生长

钌(II)配合物( Ru1 – Ru5 )，通式为[Ru(NS)(dppe) ₂ ]PF ₆，带有两个1,2-双(二苯基膦)乙烷(dppe)配体和一系列巯基配体( NS），已经开发。复合物中这些配体的组合赋予疏水性物质对五种癌细胞系的高细胞毒活性。对于 A549（肺）和 MDA-MB-231（乳腺癌）癌细胞系，与顺铂相比，复合物的 IC ₅₀值低 288 至 14 倍。此外，与 MRC-5 非肿瘤细胞系相比，复合物对 A549 和 MDA-MB-231 癌细胞系具有选择性。通过使用研究了复合物的多靶点特性小牛胸腺DNA (CT DNA)、人血清白蛋白和人拓扑异构酶 IB (hTopIB)。该复合物有效地抑制了 hTopIB。特别是，带有 4,6-二氨基-2-巯基嘧啶 (dmp) 配体的复合物 [Ru(dmp)(dppe) ₂ ]PF ₆ ( Ru3 ) 通过作用于这种酶的催化循环。分子对接表明，Ru1 - Ru5复合物通过 hTopI 和 hTopI-DNA 上的活性位点具有结合亲和力，主要通过 π-烷基和烷基疏水相互作用，以及通过氢键。络合物Ru3 在小鼠异种移植模型中显示出显着的抗鼠黑色素瘤抗肿瘤活性，但正如 Ames 和微核试验所揭示的那样，这种复合物不会损伤 DNA。