Coordination-Driven Self-Assembly Using Ditopic Pyridyl–Pyrazolyl Donor and p-Cymene Ru(II) Acceptors: [2]Catenane Synthesis and Anticancer Activities

Coordination-driven self-assembly of m-bis[3-(4-pyridyl)pyrazolyl]xylene (L) and [(p-cymene)2Ru2(OO∩OO)2(OTf)2] (A1) (OO∩OO = 6,11-dioxido-5,12-naphthacenedione) in methanol resulted in a mixture of [2]catenane 1and macrocycle 2, and self-assembly in nitromethane resulted in pure macrocycle 2, whereas the coordination-driven self-assembly of Land similar acceptors [(p-cymene)2Ru2(OO∩OO)2(OTf)2] [OO∩OO = 5,8-dioxido-1,4-naphthoquinonnato (A2); 2,5-dioxido-1,4-benzoquinonato (A3); oxalato (A4)] resulted in the formations of monomeric macrocycles 3–5, respectively. All self-assembled macrocycles were obtained in excellent yields (>90%) as triflate salts and were fully characterized by multinuclear NMR, elemental analysis, and electrospray ionization mass spectrometry (ESI-MS). The structures of [2]catenane 1and macrocycles 5were confirmed by single-crystal X-ray diffraction analysis. The X-ray structure of 1confirmed an edge-to-face interaction between the tetracene moiety in parallel-displaced π–π stacks (3.5 Å), and CH···π (2.5 Å) stabilizes the [2]catenane topology. Macrocycles 2–5were assessed for anticancer activities using human cancer cell lines of different origins, and the macrocycle 3was found to exhibit the best inhibitory effect and to do so in a dose-dependent manner. Further examination with the Tali apoptosis assay suggested the growth inhibitory effect of 3involved the induction of the programmed cell death, and this suggestion was supported by observations of PARP and caspase 3 cleavage after treating cells with 3. In addition, exposure to 3increased the expression of Bax and repressed the expression of Bcl-2, thus indicating the involvement of macrocycle 3upstream of Bax and Bcl-2 in the apoptotic signaling pathway. Macrocycle 3also tended to repress metastasis as evidenced by changes in the transcriptional expressions E- and N-cadherin (markers of metastasis). Furthermore, a stability assay demonstrated macrocycle 3remained stable at high concentration.