Effect ofN,NCoordination and Ru^IIHalide Bond in Enhancing Selective Toxicity of a Tyramine-Based Ru^II(p-Cymene) Complex

Abstract

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.

Tunable Anticancer Activity of Furoylthiourea‐Based RuII–Arene Complexes and Their Mechanism of Action

“…The tripeptide glutathione (γ‐ l ‐Glu‐ l ‐Cys‐Gly; GSH) is an abundant (m m ) intracellular thiol that is known to cause the detoxification of heavier transition‐metal ions, including several platinum and ruthenium anticancer compounds, which have an affinity towards sulfur [47] . However, Wang et al.…”

“…The tripeptide glutathione (g-l-Glu-l-Cys-Gly; GSH) is an abundant (mm)i ntracellular thiol that is known to cause the detoxification of heaviert ransition-metal ions, including several platinum and ruthenium anticancer compounds,w hich have an affinity towards sulfur. [47] However, Wang et al reported ap ossibly conflicting role of GSH in the mechanism of action of Ru IIarene complexes,w hich may contribute to the lack of cross-resistancef or platinum-based therapeutics. [48,49] The interaction of complexes C5 and C13 with GSH was studied by 1 HNMR spectroscopy;t he spectra were recorded over ap eriod of 24 h, after the addition of ak nown amount of the respective complex in [D 6 ]DMSO to a1 0-folde xcessc oncentration of GSH in D 2 O(see Figure S80 in the Supporting Information).T he experimental conditions were the same as used in the solution stability studies.…”

Tuning the Cytotoxicity of Bis-Phosphino-Amines Ruthenium(II) Para-Cymene Complexes for Clinical Development in Breast Cancer

“…In this regard, a very high number of new organometallic ruthenium agents have been reported as potential candidates for clinical translation. Many examples of the screening of mono-, di-, and poly-nuclear ruthenium compounds with biologically inactive and active auxiliar ligands to give chiral and achiral complexes have been reported by advanced biological methods to understand their mechanism of action [27][28][29][30][31][32][33][34]. In this context, successful ruthenium complexes have been reported for the treatment of breast cancer [35].…”

Synthesis, Structure and Cytotoxicity of N,N and N,O‐Coordinated RuII Complexes of 3‐Aminobenzoate Schiff Bases against Triple‐negative Breast Cancer

“…[49][50][51][52][53] Effect of halide interchange showed remarkable differences in the mechanism of action in certain iminopyridine and azopyridine based ligands and their corresponding Ru II (η 6 -p-cymene) complexes. [50,54] The iodido coordinated Ru II complexes show more kinetic inertness and better activity against various forms of cancer including A2780 (ovarian), MCF-7 (breast), HCT116 (colon) and MIA PaCa-2 (pancreatic) cell lines. Certain iodido coordinated Ru II complexes show high potency towards cisplatin-resistant ovarian cancer (A2780cisR), oxaliplatin-resistant colon cancer (HCT116Ox) and p53-null colon cancer (HCT116p53-/À ) cells suggesting p53-independent cytotoxicity.…”

“…[49] There are examples where the Ru II -iodido complexes are internalized more in cancer cells. [54][55] Among the various forms of cancer, breast cancer is the second most common cancer in the world and ranks fifth for its fatality. [56] Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic phenotype of breast cancer with a poor prognosis and high relapse rate due to the absence of three major targeting receptors estrogen, progesterone and HER2.…”