Inhibition of 3D colon cancer stem cell spheroids by cytotoxic Ru<sup>II</sup>-<i>p</i>-cymene complexes of mesalazine derivatives

Acharya, Sourav; Ghosh, Subhashis; Maji, Moumita; Parambil, Ajmal Roshan Unniram; Singh, Sandeep; Mukherjee, Arindam

doi:10.1039/d0cc00472c

Cited by 17 publications

(26 citation statements)

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“…We have synthesized and characterized a series of N,O and N,Ncoordinated Ru II complexes (1-9) with ligands having 3-aminobenzoate forming Schiff bases with five different aldehydes. Similar to our earlier reports, [65] the pyridine based N,Ncoordinated complexes are less stable, more hydrophilic and less cytotoxic (1)(2)(3)(4). The presence of a pendant free carboxylic acid group also decreased cytotoxicity ( 1 and 4).…”

Section: Discussionsupporting

confidence: 88%

“…The complexes, with the free À COOH groups, 1 and 4, were ineffective, which may be ascribed to their poor solution stability and low pK a of free acid groups making them difficult to traverse the cell membranes at the physiological pH of 7.4. [65] It may be argued that 1 has PF 6…”

Section: Resultsmentioning

confidence: 99%

“…[57] It has been found that p-cymene based Ru II complexes may be an effective choice against triple-negative breast cancer cells. [58][59][60][61][62][63][64] In our endeavors, we have generated cytotoxic Ru II -(pcymene) complexes of imidazole, benzimidazole, anthraimidazoledione and aryl trimethoxy based ligand systems, with excellent efficacy against TNBC, [53,55,[65][66][67] pancreatic cancer, [54] and colon cancer. [65] To gain further insight if the N,N vs. N,O coordination proceeds with differences in stability and cell killing pathways, we designed nine Ru II (p-cymene) complexes of 3-aminobenzoate while varying the aldehydes (pyridine-2carboxaldehyde, imidazole-2-carboxaldehyde, salicylaldehyde, 2-hydroxynaphthaldehyde and ortho-vanillin) generating ligands L1-L7.…”

Section: Introductionmentioning

confidence: 99%

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

Mukherjee

Koley

Chakraborty

et al. 2021

Chemistry An Asian Journal

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Half-sandwich Ru II complexes, [(YZ)Ru II (η 6arene)(X)] + , (YZ = chelating bidentate ligand, X = halide), with N,N and N,O coordination (1-9) show significant antiproliferative activity against the metastatic triple-negative breast carcinoma (MDA-MB-231). 3-aminobenzoic acid or its methyl ester is used in all the ligands while varying the aldehyde for N,N and N,O coordination. In the N,N coordinated complex the coordinated halide(X) is varied for enhancing stability in solution (X=Cl, I). Rapid aquation and halide exchange of the pyridine analogues, 2 and 3, in solution are a major bane towards their antiproliferative activity. Presence of free À COOH group (1 and 4) make complexes hydrophilic and reduces toxicity. The imidazolyl 3aminobenzoate based N,N coordinated 5 and 6 display better solution stability and efficient antiproliferative activity (IC 50 ca. 2.3-2.5 μM) compared to the pyridine based 2 and 3 (IC 50 > 100 μM) or the N,O coordinated complexes (7-9) (IC 50 ca. 7-10 μM). The iodido coordinated, 6, is resistant towards aquation and halide exchange. The N,O coordinated 7-9 underwent instantaneous aquation at pH 7.4 generating monoaquated complexes stable for at least 6 h. Complexes 5 and 6, bind to 9-ethylguanine (9-EtG) showing propensity to interact with DNA bases. The complexes may kill via apoptosis as displayed from the study of 8. The change in coordination mode and the aldehyde affected the solution stability, antiproliferative activity and mechanistic pathways. The N,N coordinated (5 and 6) exhibit arrest in the G2/M phase while the N,O coordinated 8 showed arrest in the G0/ G1 phase.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mukherjee

Koley

Chakraborty

et al. 2021

Chemistry An Asian Journal

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“…The complexes were synthesized according to a procedure similar to that reported by us earlier. 30 Precisely, a methanolic solution of [Ru II (p-cymene)(Cl) 2 ] 2 (30.5 mg, 0.05 mmol) or [Ru II (p-cymene)(I) 2 ] 2 (49 mg, 0.05 mmol) was added to a methanolic solution of the respective ligands (0.1 mmol) in the dark under a nitrogen atmosphere and stirred for 24 h. NH 4 PF 6 (0.15 mmol) was then added and the solution stirred for another 30 min. The solvent from the resultant mixture was evaporated under reduced pressure, and the yellow solid obtained was dissolved in cold dichloromethane and filtered to remove any excess NH 4 PF 6 .…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Effect of an Imidazole-Containing Schiff Base of an Aromatic Sulfonamide on the Cytotoxic Efficacy of N,N-Coordinated Half-Sandwich Ruthenium(II) p-Cymene Complexes

et al. 2021

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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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“…P-cymene is an extract of Eupatorium, which is the most important active ingredient and has antioxidant and antitumoral activity potentials [8][9]. Acharya et al [10] found that P-cymene can inhibited the viability and size of the HT-29 colonospheres in 3D colon cancer stem cells pheroids and do not enhance the expression of HES-1 gene, a crucial downstream gene in the Notch signalling…”

Section: Introductionmentioning

confidence: 99%

P-cymene prevent high-fat diet-associated colorectal cancer by improving the structure of intestinal flora

Jin¹,

Li²,

Zhang³

et al. 2021

J. Cancer

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Objective: To investigate the preventing effect of P-cymene on high fat diet-related colorectal cancer and its mechanism. Methods: Forty Wistar rats were randomly divided into G1 group (high-fat diet), G2 group (high-fat diet + DMH), G3 group (high-fat diet + P-cymene), and G4 group (high-fat diet + DMH + P-cymene).G2 and G4 groups were subcutaneously injected with dimethylhydrazine (DMH), and G3 and G4 groups were intragastrically administered with P-cymene to investigate the effects of P-cymene on tumor formation, inflammatory factors, glucose, lipid metabolism and gut microbes. Results: No tumors were formed in the high-fat diet group (G1) or the high-fat diet + P-cymone group (G3). 7 rats (70%) of the high-fat diet + DMH group (G2) developed 8 cancerous nodules, including 6 adenocarcinomas and 2 signet ring cell carcinomas; 4 rats (40%) in the high-fat diet + DMH + P-cymene group (G4) group formed 4 cancerous nodules, all of which were adenocarcinoma. There was no significant difference in the changes of glucose and lipid metabolism in each group. After the use of P-cymene, IL-1 decreased, IL-6 increased, and LEP decreased in the G4 group.The difference was statistically significant.The contents of Candida and Unclassified Bacteria in the G3 group rats were significantly lower than those in the G1 group.At the species level comparison, compared with the G2 group, the content of Clostridium XlVa in the intestinal tract of the G2 group rats was significantly increased compared to the G1 group. Conclusion:In this study, it was found that p-cymenen can prevent the occurrence of colorectal cancer related to high-fat and high-calorie diet. The mechanism may be is reducing the expression of inflammatory factors such as IL-1 and LEP, increasing the expression of inflammatory factors of IL-6, and promoting the growth of probiotics such as bifidobacteria, isobacteria and clostridium IV in the intestinal tract.

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Inhibition of 3D colon cancer stem cell spheroids by cytotoxic Ru^II-p-cymene complexes of mesalazine derivatives

Abstract: RuII-p-cymene complexes of imidazole–mesalazine based ligands kill bulk and stem colon cancer cells with tight regulation over stemness markers.

Cited by 17 publications

References 34 publications

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

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

Effect of an Imidazole-Containing Schiff Base of an Aromatic Sulfonamide on the Cytotoxic Efficacy of N,N-Coordinated Half-Sandwich Ruthenium(II) p-Cymene Complexes

P-cymene prevent high-fat diet-associated colorectal cancer by improving the structure of intestinal flora

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Inhibition of 3D colon cancer stem cell spheroids by cytotoxic RuII-p-cymene complexes of mesalazine derivatives

Abstract: RuII-p-cymene complexes of imidazole–mesalazine based ligands kill bulk and stem colon cancer cells with tight regulation over stemness markers.

Cited by 17 publications

References 34 publications

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

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

Effect of an Imidazole-Containing Schiff Base of an Aromatic Sulfonamide on the Cytotoxic Efficacy of N,N-Coordinated Half-Sandwich Ruthenium(II) p-Cymene Complexes

P-cymene prevent high-fat diet-associated colorectal cancer by improving the structure of intestinal flora

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Inhibition of 3D colon cancer stem cell spheroids by cytotoxic Ru^II-p-cymene complexes of mesalazine derivatives

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

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