Iodo coordinated half-sandwich RuII-anthraimidazoldione shows stability and low cytotoxicity even under hypoxia in metastatic cancer MDA-MB-231 cells (1–2 μM), induces apoptosis without ROS, and prevents migration at IC20 dose.
Four trimethoxy-and dimethoxyphenylamine-based Schiff base (L1−L4)-bearing Ru II −p-cymene complexes (1−4) of the chemical formula [Ru II (η 6 -p-cymene)(L)(Cl)] were synthesized, isolated in pure form, and structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The complexes showed excellent in vitro antiproliferative activity against *
Ruthenium compounds are promising anticancer candidates owing to their lower side-effects and encouraging activities against resistant tumors. Half-sandwich piano-stool type Ru II compounds of general formula [(L)Ru II (η 6 -arene)(X)] + (L = chelating bidentate ligand, X = halide) have exhibited significant therapeutic potential against cisplatin-resistant tumor cell lines. In Ru II (p-cymene) based complexes, the change of the halide leaving group has led to several interesting features, viz., hydrolytic stability, resistance toward thiols, and alteration in pathways of action. Tyramine is a naturally occurring monoamine which acts as a catecholamine precursor in humans. We synthesized a family of N,N and N,O coordinated Ru II (p-cymene) complexes, [(L)-Ru II (η 6 -arene)(X)] + (1−4), with tyramine and varied the halide (X = Cl, I) to investigate the difference in reactivity. Our studies showed that complex 2 bearing N,N coordination with an iodido leaving group shows selective in vitro cytotoxicity against the pancreatic cancer cell line MIA PaCa-2 (IC 50 ca. 5 μM) but is less toxic to triple-negative breast cancer (MDA-MB-231), hepatocellular carcinoma (Hep G2), and the normal human foreskin fibroblasts (HFF-1). Complex 2 displays stability toward hydrolysis and does not bind with glutathione, as confirmed by 1 H NMR and ESI-HRMS experiments. The inert nature of 2 leads to enhancement of cytotoxicity (IC 50 = 5.3 ± 1 μM) upon increasing the cellular treatment time from 48 to 72 h.
Sulfonamides have a broad range of therapeutic applications, which include the inhibition of various isoforms of carbonic anhydrases (CAs). Among the various CA isoforms, CA IX is overexpressed in tumors and regulates the pH of the tumor microenvironment. Herein we present five new ruthenium(II) p-cymene complexes (1−5) of Schiff base ligands (L1−L4) of 4-(2-aminoethyl)benzenesulfonamide by varying the aldehyde to enhance the selective cytotoxicity toward cancer cells. All of the complexes are stable to aquation for the observed period of 24 h except 1, which aquated within 1 h, but the monoaquated species is stable for 24 h. The two imidazole derivatives, 1 and 2, are cytotoxic to the cancer cells MDA-MB-231 and MIA PaCa-2 but not to the noncancerous cells CHO and MDCK. The enhanced toxicity in hypoxia against MDA-MB-231 may be due to the greater expression of CA IX in hypoxia, as per the immunofluorescence data. The most cytotoxic complexes, 1 and 2, are lipophilic, whereas 3−5 show high hydrophilicity and are not cytotoxic up to 200 μM. Complexes 1 and 2 also show a higher cellular accumulation in MDA-MB-231 than the nontoxic yet solution-stable complex 5. The cytotoxic complexes bind with the model nucleobase 9-ethylguanine but have slow reactivity toward cellular tripeptide glutathione. Both 1 and 2 induce apoptosis by depolarizing the mitochondrial membrane potential and arrest the cell cycle in the SubG1 phase.
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