Nanoencapsulation of Ruthenium Complex Ru(ThySMet): A Strategy to Improve Selective Cytotoxicity Against Breast Tumor Cells in 2D and 3D Culture Models.

BACKGROUND: Ruthenium complexes have shown promise in treating many cancers, including breast cancer. Previous studies of our group have demonstrated the potential of the trans-[Ru(PPh3)2(N,N-dimethylN'-thiophenylthioureato-k2O,S)(bipy)]PF6 complex, the Ru(ThySMet), in the treatment of breast tumor cancers, both in 2D and 3D culture systems. Additionally, this complex presented low toxicity when tested in vivo. AIMS: Improve the Ru(ThySMet) activity by incorporating the complex into a microemulsion (ME) and testing its in vitro effects. METHODS: The ME-incorporated Ru(ThySMet) complex, Ru(ThySMet)ME, was tested for its biological effects in two- (2D) and three-dimensional (3D) cultures using different types of breast cells, MDA-MB-231, MCF-10A, 4T1.13ch5T1 and Balb/C 3T3 fibroblasts. RESULTS: An increased selective cytotoxicity of the Ru(ThySMet)ME for tumor cells was found in 2D cell culture, compared with the original complex. This novel compound also changed the shape of tumor cells and inhibited cell migration with more specificity. Additional 3D cell culture tests using the non-neoplastic S1 and the triple-negative invasive T4-2 breast cells have shown that Ru(ThySMet)ME presented increased selective cytotoxicity for tumor cells compared with the 2D results. The morphology assay performed in 3D also revealed its ability to reduce the size of the 3D structures and increase the circularity in T4-2 cells. CONCLUSION: These results demonstrate that the Ru(ThySMet)ME is a promising strategy to increase its solubility, delivery, and bioaccumulation in target breast tumors.

The trans-[Ru(PPh3)2(N,N-dimethyl-N'-thiophenylthioureato-k2O,S)(bipy)]PF6 complex has pro-apoptotic effects on triple negative breast cancer cells and presents low toxicity in vivo.

Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh3)2(N,N-dibutyl-N'-benzoylthioureato-k2O,S)(2,2'-bipyridine (bipy))]PF6(1), trans-[Ru(PPh3)2(N,N-dimethyl-N'-thiophenylthioureato-k2O,S)(bipy)]PF6(2) and trans-[Ru(PPh3)2(N,N-dimethyl-N'-benzoylthioureato-k2O,S)(bipy)]PF6(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice.

Probing the relationships between molecular conformation and intermolecular contacts in N,N-dibenzyl-N'-(furan-2-carbonyl)thiourea.

In the crystal structure of the title compound, C(20)H(18)N(2)O(2)S, molecules are linked by bifurcated C-H···O hydrogen-bond interactions, giving rise to chains whose links are composed of alternating centrosymmetrically disposed pairs of molecules and characterized by R(2)(2)(10) and R(2)(2)(20) hydrogen-bonding motifs. Also, N-H···S hydrogen bonds form infinite zigzag chains along the [010] direction, which exhibit the C(4) motif. Hirshfeld surface and fingerprint plots were used to explore the intermolecular interactions in the crystal structure. This analysis confirms the important role of C-H···O hydrogen bonds in the molecular conformation and in the crystal structure, providing a potentially useful tool for a full understanding of the intermolecular interactions in acylthiourea derivatives.

N-Benzoyl-N',N'-dimethyl-thio-urea.

In the title compound, C(10)H(12)N(2)OS, the amide NCO group is twisted relative to the thio-ureido SCN(2) group, forming a dihedral angle of 55.3 (2)°. The crystal packing shows inter-molecular N-H⋯S and weak C-H⋯O inter-actions, the former giving rise to the formation of centrosymmetric R(2) (2)(8) dimers.

cis-Bis[N-(2-furoyl)-N',N'-diphenyl-thio-ureato-κO,S]nickel(II).

In the title compound, [Ni(C(18)H(13)N(2)O(2)S)(2)], the Ni(II) atom is coordinated by the S and O atoms of two N-furoyl-N',N'-diphenyl-thio-ureate ligands in a slightly distorted square-planar coordination geometry. The two O and two S atoms are cis to each other.

Tris(N-benzoyl-N',N'-diphenyl-thio-ureato-κO,S)cobalt(III).

In the title compound, [Co(C(20)H(15)N(2)OS)(3)], the Co(III) atom is coordinated by the S and O atoms of three N-benzoyl-N',N'-diphenyl-thio-urea ligands in a slightly distorted octa-hedral geometry. The O and S atoms are in cis positions, while the positions between the O and S atoms are trans.

Tris[N-(2-furoyl)-N,N'-diphenyl-thio-ureato-κO,S]cobalt(III).

In the title compound, [Co(C(18)H(13)N(2)O(2)S)(3)], the Co(III) atom is coordinated by the S and O atoms of three N-furoyl-N',N'-diphenyl-thio-urea ligands in a slightly distorted octa-hedral geometry. The three O atoms are arranged fac, as are the three S atoms.