Study on Antitumor Platinum(II) Complexes of Chiral Diamines with Dicyclic Species as Steric Hindrance

A series of platinum­(II) complexes, characteristic of chiral <i>trans</i>-bicyclo­[2.2.2]­octane-7,8-diamine as ligand possessing dicyclic steric hindrance, were designed and synthesized. Biological evaluation showed that almost all complexes had cytotoxic activity against the tested cancer cell lines, among which most of chiral (<i>R</i>,<i>R</i>)-enantiomeres had stronger cytotoxicity than their (<i>S</i>,<i>S</i>)-counterparts, and <b>2a</b>, [<i>trans</i>-bicyclo­[2.2.2]­octane-7<i>R</i>,8<i>R</i>-diamine]­(oxalato-<i>O</i>,<i>O</i>′)­platinum­(II), is the most effective agent. Significantly, its counterpart, <b>2b</b>, was much more sensitive to cisplatin resistant SGC7901/CDDP cancer cell line at a higher degree than <b>2a</b>. Docking study and agarose gel electrophoresis revealed that the interaction of <b>2a</b> with DNA was similar to that of oxaliplatin. Western blot analysis demonstrated that <b>2a</b> could induce a better effect than cisplatin on a mitochondrial-dependent apoptosis pathway. Kinetic study indicated that the dicyclic ligand can accelerate the reaction rate of the complex

Design, Synthesis, and Biological Features of Platinum(II) Complexes with Rigid Steric Hindrance

A series of platinum­(II) complexes, with N-monosubstituted 1<i>R</i>,2<i>R</i>-diaminocyclohexane bearing methoxy-substituted benzyl groups as carrier ligands, were designed and synthesized. The newly prepared compounds, with chloride anions as leaving groups, were found to be very active against the tested cancer cell lines, including a cisplatin-resistant cell line. Despite their efficacy against tumor cells, they also showed low toxicity to a human normal liver cell line. Among them, complex <b>1</b> had superior cytotoxic activity against A549, HCT-116, MCF-7, SGC7901, and SGC7901/CDDP cancer cell lines. The DNA binding assay is of further special interest, as an unusual monofunctional binding mode was found, due to the introduction of a rigid substituted aromatic ring in the 1<i>R</i>,2<i>R</i>-diaminocyclohexane framework as steric hindrance. The linkage of complex <b>1</b> with DNA was stable and insensitive to nucleophilic attack. Moreover, studies including cellular uptake, gel electrophoresis, apoptosis and cell cycle, and Western blot analysis have provided insight into the high potency of this compound

Table1_Differential expression of cyclins CCNB1 and CCNG1 is involved in the chondrocyte damage of kashin-beck disease.DOCX

The purpose of this study was clarify the relationship between the differential expression of cyclins CCNB1 and CCNG1 and chondrocyte damage in Kashin-Beck disease. Systematic review and high-throughput sequencing of chondrocytes derived from Kashin-Beck disease patients were combined to identify the differentially expressed cyclins and cyclin-dependent kinase genes. In parallel, weaned SD rats were treated with low selenium for 4 weeks and then T-2 toxin for 4 weeks. Knee cartilage was collected to harvest chondrocytes for gene expression profiling. Finally, the protein expression levels of CCNB1 and CCNG1 were verified in knee cartilage tissue of Kashin-Beck disease patients and normal controls by immunohistochemical staining. The systematic review found 52 cartilage disease-related cyclins and cyclin-dependent kinase genes, 23 of which were coexpressed in Kashin-Beck disease, including 15 upregulated and 8 downregulated genes. Under the intervention of a low selenium diet and T-2 toxin exposure, CCNB1 (FC = 0.36) and CCNG1 (FC = 0.73) showed a downward expression trend in rat articular cartilage. Furthermore, compared to normal controls, CCNB1 protein in Kashin-Beck disease articular cartilage was 71.98% and 66.27% downregulated in the superficial and middle zones, respectively, and 12.06% upregulated in the deep zone. CCNG1 protein was 45.66% downregulated in the superficial zone and 12.19% and 9.13% upregulated in the middle and deep zones, respectively. The differential expression of cyclins CCNB1 and CCNG1 may be related to articular cartilage damage in Kashin-Beck disease.</p

Image1_Differential expression of cyclins CCNB1 and CCNG1 is involved in the chondrocyte damage of kashin-beck disease.JPEG

The purpose of this study was clarify the relationship between the differential expression of cyclins CCNB1 and CCNG1 and chondrocyte damage in Kashin-Beck disease. Systematic review and high-throughput sequencing of chondrocytes derived from Kashin-Beck disease patients were combined to identify the differentially expressed cyclins and cyclin-dependent kinase genes. In parallel, weaned SD rats were treated with low selenium for 4 weeks and then T-2 toxin for 4 weeks. Knee cartilage was collected to harvest chondrocytes for gene expression profiling. Finally, the protein expression levels of CCNB1 and CCNG1 were verified in knee cartilage tissue of Kashin-Beck disease patients and normal controls by immunohistochemical staining. The systematic review found 52 cartilage disease-related cyclins and cyclin-dependent kinase genes, 23 of which were coexpressed in Kashin-Beck disease, including 15 upregulated and 8 downregulated genes. Under the intervention of a low selenium diet and T-2 toxin exposure, CCNB1 (FC = 0.36) and CCNG1 (FC = 0.73) showed a downward expression trend in rat articular cartilage. Furthermore, compared to normal controls, CCNB1 protein in Kashin-Beck disease articular cartilage was 71.98% and 66.27% downregulated in the superficial and middle zones, respectively, and 12.06% upregulated in the deep zone. CCNG1 protein was 45.66% downregulated in the superficial zone and 12.19% and 9.13% upregulated in the middle and deep zones, respectively. The differential expression of cyclins CCNB1 and CCNG1 may be related to articular cartilage damage in Kashin-Beck disease.</p