An insight into porphyrin carbamate derivatives and a Cu(II) metalloporphyrin as G-quadruplex binder: Synthesis, single crystal characterization, binding ability and anti-tumor potential

Telomere with a G-quadruplex (Gq) structure is a recognized anti-tumor target. It was found that the aromatic plane of porphyrin may form π-π interactions with the Gq structure and the coordination of metal ions to porphyrin may increase its aromatic plane. Therefore, in this work, two porphyrin carbamate derivatives (1 and 2) and a Cu(II) metalloporphyrin (1-Cu) were designed and synthesized. The single crystals of 1 and 1-Cu were obtained and characteristics related to the binding interactions were analyzed at molecular level. With further Hirshfeld surface, molecular electrostatic potential, and frontier molecular orbital analyses, it was revealed that porphyrin ring, phenyl carbamate side chain and the coordinated copper ion may form synergistic binding forces with the Gq structure. Subsequently, binding ability and binding mode were tested with UV–Vis, fluorescence, and circular dichroism spectroscopies and PCR-stop method. Result showed that all three compounds selectively bound to Gq with the highest binding constant of 3.19 × 10⁷, which was an order of magnitude higher than those to the duplex DNA. Further molecular docking and molecular dynamics simulations supported the synergistic end stacking and groove binding modes. At last, anti-tumor potentials were evaluated with cytotoxicity, cell staining, cell apoptosis, and cell migration assays. Results showed that compared with the positive control drug, the IC₅₀ values of 1 and 1-Cu to the tumor cells were significantly lower, and their cytotoxicities to tumor cells were much higher than those to normal cells. Therefore, this work provided important information for designing novel drugs targeting Gq telomere.