Differences in Stability, Cytotoxicity, and Mechanism of Action of Ru(II) and Pt(II) Complexes of a Bidentate N,O Donor Ligand

Abstract

We report [RuII(L)­(η6-p-cym)­Cl] (1 and 2) and [PtII(L)­(DMSO)­Cl] (3 and 4) complexes, where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde (HL1) or o-vanillin (HL2). The complexes were characterized by single-crystal X-ray diffraction and other analytical techniques. The 1H nuclear magnetic resonance data show that both the Ru­(II) and Pt­(II) complexes start forming the aquated complex within an hour. The aquated complexes are stable at least up to 24 h. The complexes bind to the N7 of the model nucleobase 9-ethylguanine (9-EtG). Interaction with calf thymus (CT) DNA shows moderate binding interactions with binding constants, K b (3.7 ± 1.2) × 103 M–1 and (4.3 ± 1.9) × 103 M–1 for 1 and 3, respectively. The complexes exhibit significant antiproliferative activity against human pancreas ductal adenocarcinoma (Mia PaCa-2), triple negative metastatic breast adenocarcinoma (MDA-MB-231), hepatocellular carcinoma (Hep G2), and colorectal adenocarcinoma (HT-29) cell lines. The studies show that with the same ligand the Pt­(II) complexes are more potent than the Ru­(II) complexes. The in vitro potencies of all the complexes toward pancreatic cancer cell line MIA PaCa-2 are more than cisplatin (CDDP). The Pt­(II) and Ru­(II) complexes show similar binding constants with CT-DNA, but the reactivity of the Pt­(II) complex 3 with 9-EtG is faster and their overall cell killing pathways are different. This is evident from the arrest of the cell cycle by the Ru­(II) complex 1 in the G2/M phase in contrast to the SubG1 phase arrest by the Pt­(II) complex 3. The immunoblot study shows that 3 increases cyclin D and Bcl-2 expression in MDA-MB-231 due to the SubG1 phase arrest where these proteins express in greater quantities. However, both 1 and 3 kill in the apoptotic pathway via dose-dependent activation of caspase 3. Complex 3 depolarizes the mitochondria more efficiently than 1, suggesting its higher preference for the intrinsic pathway of apoptosis. Our work reveals that the same bidentate ligand with a change of the metal center, viz, Pt­(II) or Ru­(II), imparts significant variation in cytotoxic dosage and pathway of action due to specific intrinsic properties of a metal center (viz, coordination geometry, solution stability) manifested in a complex.

Synthesis, Biomacromolecular Interactions, Photodynamic NO Releasing and Cellular Imaging of Two [RuCl(qn)(Lbpy)(NO)]X Complexes

“…A series of ruthenium complexes containing the different ligands against cancer cells have been reported, these complexes could be used to reduce tumor growth, and some complexes could increase mean survival time with a relatively low cytotoxicity and genotoxicity in non-tumor cells [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. The studies on the Ru complexes with multi-mixed ligands provide a strategy to search for effective leading compound and shed light on the mechanism of action.…”

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

“…CDCl3, DMSO-d 6 , and D2O were stored over activated 4 Å molecular sieves and degassed by several freeze-thaw cycles. All NMR experiments were conducted in deuterated solvents at 297 K in a Varian FT-400 spectrometer (VARIAN Inc., Palo Alto, California, USA) equipped with a 4 nucleus ASW PFG 1 H/ 19 F/ 13 C/{ 15 N- 31 P}. The 1 H π/2 pulse length was adjusted for each sample.…”

“…1 H-and 13 C{ 1 H}-NMR chemical shifts (δ) are given in ppm relative to TMS. 31 P{ 1 H}-NMR chemical shifts are given in ppm relative to H3PO4 (85%). Coupling constants (J) are documented in Hz.…”

“…Monitoring by NMR showed all starting materials to have been consumed within 5 h; at this point, the solution was filtered to remove the Et 3 NHCl formed. On removing all volatiles under reduced pressure, the resultant white solid was repeatedly washed with degassed MeCN until no Ph 2 PP(O)Ph 2 impurity could be detected by 31 P{ 1 H}-NMR.…”

“…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].…”