RuII (p-cymene) complexes of tyramine and 3-amino benzoate based Schiff bases: Effect on halide variation, N,N and N,O coordination on cytotoxicity and pathway of action

Mukherjee, Arpan (2022) RuII (p-cymene) complexes of tyramine and 3-amino benzoate based Schiff bases: Effect on halide variation, N,N and N,O coordination on cytotoxicity and pathway of action. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Arpan Mukherjee (14RS025)) 14RS025_DCS.pdf - Submitted Version Restricted to Repository staff only Download (8MB)

Abstract

The research work presented in this thesis is based upon design of RuII (p-cymene) complexes to investigate the effects of halide variation and change in coordination mode upon cytotoxicity and pathways of action. In RuII (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. In Chapter II, we synthesized a family of N,N and N,O coordinated RuII (p-cymene) complexes (II-1to II-4) with tyramine and varied the halide (X=Cl, I) to investigate the difference in reactivity. Our studies showed that complex II-2 bearing N,N coordination with an iodido leaving group has selective in vitro cytotoxicity against the pancreatic cancer cell line, MIA PaCa-2 (IC50 ca. 5 μM), but is less toxic to triplenegative breast cancer (MDA-MB-231), hepatocellular carcinoma (Hep G2) and the normal human foreskin fibroblasts (HFF-1). In an attempt to explore the change in cytotoxicity pattern upon alteration of coordination from N,N to N,O, the monomethyl ester of 3-amino benzoic acid was utilized for Schiff base preparation with salicylaldehyde, 2-hydroxy naphthaldehyde and ortho-vanillin (V-L1, V-L2 and V-L3 respectively), in Chapter V. The corresponding N,O coordinated RuII (p-cymene) complexes (V-1 to V-3) of these ligands were obtained in substantial yields. Introduction of the 2-hydroxynaphthyl group in V-2, enhanced its lipophilicity and cytotoxicity (IC50 ca. 7 μM) as compared to the salicylaldehyde and ortho-vanillin analogues (IC50 ca. 10 μM). The N,O coordinated complexes , V-1 to V-3, underwent instant aquation at the physiological pH of 7.4, generating mono-aquated complexes, stable for at least 6 h. Complex V-2 arrests MDA-MB- 231 cells in the G0/G1 phase and also kills via apoptosis. Thus, esterification and subtle variation of the aldehyde groups, accompanied by change in coordination mode from N,N to N,O (from Chapter IV) lead to interesting cytotoxicity profiles. Our studies from Chapter IV suggest that the cytotoxic potential improves in N,N coordinated complexes compared to their neutral N,O counterparts when the imidazole motif is present in the former. Thus, we show that proper ligand choice render N,N coordinated RuII (p-cymene) complexes ca. 3-4 times more cytotoxic than N,O coordinated analogues. Change in cell cycle arrest pathway upon coordination environment alteration, as presented throughout the study of these two chapters is also a distinctive proof of the designed complexes following different action pathways.

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