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

Abstract

Coordination-driven self-assembly of m-bis[3-(4-pyridyl)pyrazolyl]xylene (L) and [(p-cymene)(2)Ru-2-(OO boolean AND OO)(2)(OTf)(2)] (A(1)) (OO boolean AND OO = 6,11-dioxido-5,12-naphthacenedione) in methanol resulted in a mixture of [2]catenane 1 and macrocyde 2, and self-assembly in nitromethane resulted in pure macrocycle 2, whereas the coordination-driven self-assembly of L and similar acceptors [(p-cymene)(2)Ru-2(OO boolean AND OO)(2)(OTf)(2)] [OO boolean AND OO = 5,8-dioxido-1,4-naphthoquinonnato (A(2)); 2,5-dioxido-1,4-benzoquinonato (A(3)); oxalato (A(4))] resulted in the formations of monomeric macrocydes 3-5, respectively. All self-assembled macrocydes 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 1 and macrocydes 5 were confirmed by single-crystal X-ray diffraction analysis. The X-ray structure of 1 confirmed an edge-to-face interaction between the tetracene moiety in parallel-displaced pi-pi stacks (3.5 angstrom), and CH center dot center dot center dot pi (2.5 angstrom) stabilizes the [2]catenane topology. Macrocydes 2-5 were assessed for anticancer activities using human cancer cell lines of different origins, and the macrocyde 3 was 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 3 involved 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 3 increased the expression of Bax and repressed the expression of Bcl-2, thus indicating the involvement of macrocyde 3 upstream of Bax and Bcl-2 in the apoptotic signaling pathway. Macrocycle 3 also tended to repress metastasis as evidenced by changes in the transcriptional expressions E- and N-cadherin (markers of metastasis). Furthermore, a stability assay demonstrated macrocyde 3 remained stable at high concentration.