One pot three component synthesis of DNA targeting phototoxic Ru(ii)-p-cymene dipyrido[3,2-a:2′,3′-c]phenazine analogues

Abstract

We have developed a One pot three component synthetic protocol for half-sandwich Ru(II)-p-cymene dipyrido[3,2-a:2',3'-c]phenazine analogues for selective cancer therapy under light irradiation. On average, the cytotoxicity of all the complexes...

Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity

“…On the other hand, the protons in the para position as well as the phenazine protons remained largely unaffected. Similar observations were previously reported for other Ru-dppz complexes . For example, in the uncoordinated ligand A , the signals of H2(H2′) and H4(H4′) protons appeared at 9.47 and 9.16 ppm, respectively.…”

“…The observed isotopic distribution pattern was in good agreement with the calculated mass distribution. Analysis of the NMR spectra revealed that the chemical shifts of the protons and carbons of the Ru complexes were in agreement with the previously published structurally similar compounds. , As expected, the arene-to-ligand ratio was found to be 1:1 as determined by the integration of protons in the 1 H NMR spectra. The six protons originated from the benzene moiety in complexes 1A – 1C were located at 6.35 ppm.…”

“…It should be noted that it was previously reported that dppz and its analogues were devoid of any anticancer activity against different cancer cell lines, ,, with the exception of ligand A , which was moderately cytotoxic against the HeLa cell line (IC 50(24 h) ≈ 60 μM) . The majority of the tested Ru complexes exhibited improved aqueous solubility but modest anticancer activity, similar to previously published Ru-dppz complexes. ,,,,,, Only 3A and 3C were cytotoxic in the low micromolar range in MDA-MB-231 and HCT116 cell lines in agreement with their higher aqueous stability. Interestingly, most of the tested compounds did not show any effects in the murine colon cancer CT26 cell line, indicating their selectivity toward human cancer cell lines.…”

“…In cancer cells, ROS production is elevated due to their higher metabolic rate compared to normal cells . Various structurally different Ru complexes were shown to induce ROS-mediated cancer cell death. , However, typically ROS experiments were carried out after prolonged drug exposure (12–48 h); , thus, the ROS observed in drug-treated cancer cells might be the consequence of cell damage caused by other mechanisms. Based on the results of cyclic voltammetry experiments, 1A – 3A , 1B , 2B , and 1C – 3C were electrochemically active, and the biologically accessible reduction was dppz ligand-based.…”

“…In general, the coordination of dppz-derived ligands to the Ru­(polypyridyl) backbone yields highly stable Ru complexes that are inert under physiological conditions. , On the other hand, the use of organometallic fragments typically leads to the formation of half-sandwich metal-dppz complexes with labile chlorido ligands. , It is believed that the hydrolysis of the labile ligands results in the formation of highly reactive solvato complexes that readily bind to the DNA, leading to DNA degradation. Therefore, various half-sandwich Ru complexes with dppz ligands and its analogues demonstrated promising anticancer activity, which was dependent on their reactivity and interactions with biomolecules.…”