Enhancing the Cytotoxicity of Mesalazine based Ru(II)-p-Cymene Complexes towards NOTCH1 overexpressed Oral squamous cell carcinoma

Kumari, Pragya (2021) Enhancing the Cytotoxicity of Mesalazine based Ru(II)-p-Cymene Complexes towards NOTCH1 overexpressed Oral squamous cell carcinoma. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Pragya Kumari (16MS057)) 16MS057_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (7MB)

Abstract

A series of mesalazine and 3-aminobenzoic acid-based metal complexes were synthesized and characterized to gain deeper insight into the possibilities to enhance cytotoxic efficacy towards NOTCH1 intracellular domain (NICD) overexpressing Oral Squamous Cell Carcinoma (OSCC) named SCC070-hICN-GFP. The SCC070-hICN-GFP cells have green fluorescent protein tagged to distinguish them separately from others. The six half sandwich Ru(II) p-cymene complexes (1-6) vary in terms of the presence or absence of a phenolic -OH, which we wanted to know if is an essential part of the scaffold. In addition, we also increased and decreased the lipophilicity by making ethyl ester and hydroxamic acid derivatives of the carboxylate at the 3-position in the benzene ring with respect to the -NH2 group. Complexes 1-4 are the ester derivatives, and they are hydrolytically more stable at physiological pH than the hydroxamic acid derivative-based complexes 5 and 6. Interestingly, the Ru(II) iodidio complexes of the ethyl-ester based ligands (L1 and L2) are more stable than the chlorido ones. However, the presence of the Ru(II) iodidio does not enhance the lipophilicity. The in vitro antiproliferative activity towards the triple-negative breast carcinoma (MDA-MB-231) remains similar to the earlier reported mesalazine based Ru(II) complexes of the methyl ester derivative. Albeit, 1-4 show at least two-fold better antiproliferative activity against the NOTCH1 overexpressed SCC070-hICN-GFP. NOTCH1 plays an important role in maintaining stemness of cancer cells controlling metastasis and tumor relapse. Thus, this result shows a significant improvement in dose efficacy. In addition, the 3-aminobenzoic acid analogs 1 and 3 with phenolic -OH group absent, show similar activity as 2 and 4. The most lipophilic ethyl ester-based ruthenium(II) complexes 1-4 with logDo/w in the range of 2-3, exhibit half-maximal inhibitory activity concentration (IC50) in the micromolar range (1.1 μM to 2.8 μM) against tested cancer cells, while the hydrophilic hydroxamic acid-based ruthenium(II) complexes 5 and 6 are inactive. The inactivity of the hydroxamic acid based complexes may be due to a combination of their higher hydrophilicity and poorer stability in aqueous medium at pH 7.4. Thus, the phenolic -OH in the mesalazine has no major role in the in vitro antiproliferative activity of the complexes whereas, the presence of an ethyl ester improves dose efficacy to kill the NOTCH1 overexpressing cells.

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