Synthetic Methodologies to Design Metal Complexes of Orotic Acid and Ambroxol to Enhance Specificity against Liver and Lung Cancer

Maity, Dipayan (2022) Synthetic Methodologies to Design Metal Complexes of Orotic Acid and Ambroxol to Enhance Specificity against Liver and Lung Cancer. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Dipayan Maity (17MS183)) 17MS183_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (2MB)

Abstract

By definition, “Cancer” is uncontrolled cell growth. When certain gene mutations destroy the balance between gene activities that promote cell proliferation and those that suppress it, the cells undergo uncontrolled proliferation and become cancerous, they even evade apoptosis. By the cell/tissue types, there are six major types of cancer, i.e., Carcinoma, Sarcoma, Myeloma, Lymphoma, Leukemia, and Blastoma. Cancer stem cells, also known as CSCs are a set of stem cells with regeneration, metastasizing and differentiating capability. This makes them an important factor in understanding cancer growth and designing cancer therapeutic approaches. Orotic Acid (OA) and Ambroxol (AMBL) are two molecules with a close connection to liver cancer and lung cancer respectively. Synthesis of a series of orotic acid derivatives were designed and tried by modifying the acid group in it and for that Orotic Acid (R1), as the main substrate of interest, was subjected to reactions with different spacers, i.e., several diamines (A1, A2) and amino-alcohol (A3) under various reaction conditions to understand the feasibility of functionalization of acid moiety in R1 and synthesize a derivative of R1 with the capability of linking with a fluorescent dye in order to gain insight on the uptake of orotic acid selectively in liver cancer cell lines. There being very few literatures on Orotic acid modification, the study was very open-handed. However, all the trials gave negative results where the reagents are either breaking down into fragments being unstable in a particular scenario or it is generating unidentifiable product species which was inconclusive. The starting materials had several problems itself to begin with; in most cases, the Mass data and NMR report showed no presence of either reagent or any expected product. Multiple trials according to the proposed schemes, all yielded side products or inconclusive results. Synthesis of P4 was done following a reported protocol. But synthesis of P5 from P4 according to proposed scheme was unsuccessful. The was no previous protocol regarding Scheme 2.4 and again, there was an observation of reagent fragments in NMR report and mass spectra. The solubility issue of Orotic acid caused a huge problem in reaction procedures and all the trial schemes failed to produce any positive result with functionalization of Orotic acid Different pathways need to be explored for functionalizing Orotic acid. A series of Ambroxol ligand (L1) and its Schiff base ligand (L2, L3) based Ruthenium (II) metal complexes have been designed to study the cytotoxicity and specificity of Ambroxol based metal complexes to gain insight into the potential of Ambroxol in fighting lung cancer and standardize protocols for synthesizing pure Ru(II) complexes with one or more Ambroxol moiety as Ligands. There has been no previous report of Ru(II/III) or Pt(II/IV) complexes of Ambroxol to its Schiff bases (L2, L3). To synthesize pure Ambroxol based Ru(II) complexes, different reaction schemes have been designed and tried out with Ru(II) precursors (Ru4, Ru5) as the primary starting material besides Ambroxol (L1). While Scheme 3.1 gave positive results on the synthesis of metal complex M1, reaction based on Scheme 3.2 resulted in a very different scenario. Ru(II) complex M1 was synthesized but couldn’t be isolated as a pure metal complex following Scheme 3.1. Scheme 3.3 also showed the feasibility of the synthesis, but isolation was impossible. Similarly, the synthesis of Schiff bases L2 and L3 faced many challenges, and in the case of L2, no suitable environment was found to facilitate the reaction between Ambroxol (L1) and Isatin (C2). The other Schiff base L3 was attempted, but the pure compound could not be isolated. It was observed that synthesis of M1 in planar geometry is possible, but the purification is the main problem, while M2 with octahedral geometry has some uncertainty, and the scheme didn’t succeed. This study gave a handful of insights into the reactivity and plausibility of Ambroxol based metal complex synthesis. The tried synthesis methods for Orotic acid derivatives (P1, P2, P5) showed the hurdles with the functionalization of acid moiety in Orotic Acid (R1) and how it behaves in different conditions. It showed some result in the context of feasibility of the synthesis with HATU, but the result was inconclusive and showed that adding a spacer is not possible if the reaction environment is acidic, as the NMR showed the broken pieces of starting materials. Using Ambroxol as a ligand seems to be an interesting approach towards synthesizing cytotoxic metal complexes, however separating the pure metal complex (M1) was a major hurdle that couldn’t be solved in the due time. On the other hand, Schiff base of Ambroxol (L1) and Isatin (C2) isn’t feasible in any reaction condition.

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