Synthesis and characterisation of novel azamacrocyclic chelators for biomedical applications : biological activity and radiolabelling

Al-Zirgani, Ali Saynak Zigair

Abstract

Azamacrocyclic derivatives that contain nitrogen donors have been used for decades in analytical, industrial and medical applications. They are good hosts for metal ions, anions, neutral molecules and organic cation guests. Azamacrocyclic complexes that are biologically active have been used in the identification of diseased tissues. Transition metal macrocyclic complexes have also received significant attention due to their pharmacological properties such as toxicity against bacterial and fungal growth. Many macrocyclic complexes have been reported to have anti-inflammatory properties.
A number of azamacrocyclic ligands have been used in the design of bifunctional chelators (BFCs) that have been utilised in molecular imaging. Incorporation of a positron emitting metal radioisotope such as 68Ga requires a BFC to form a stable complex in vivo and for covalent bond formation (conjugation) with a targeting moiety. Macrocyclic complexes are essential to a number of biological systems and have shown affinity for the CXCR4 chemokine receptor. Studies confirmed that CXCR4 is an important factor in the migration, invasiveness, proliferation and metastasis of tumours and overexpression of CXCR4 has been shown in twenty three different human tumours including non-small cell lung cancer, ovarian cancer, prostate cancer, colorectal cancer and breast cancer.
In this work three different classes of azamacrocycles have been synthesised. The first group is a series of configurationally restricted copper(II), zinc(II) and nickel(II) mono-ring macrocycles bearing benzimidazole derivatised pendant arms. The antifungal activity has been determined for both ligands and their transition metal complexes. Most of the compounds tested showed a recognisable activity. The zinc(II) complexes of the ligands (side-bridged cyclen benzimidazole and side-bridged cyclen 4-nitrobenzyl benzimidazole) showed the highest antifungal activity of the compounds tested.
The second class of azamacrocyclic derivatives synthesised comprises five novel bifunctional chelators based on benzimidazole TACN and NO2A derivatives. Four 68Ga complexes of the following ligands: NO2A benzimidazole, TACN tris 4-nitrobenzyl benzimidazole, NO2A 4-nitrobenzyl benzimidazole and NO2A 4-aminobenzyl benzimidazole, have been synthesised in radiochemical yields of 73%, 55%, 25% and 37% respectively at RT with a 5 minute reaction time.
The third type of azamacrocyclic ligands are C-functionalised bis-tetraazamacrocyclic derivatives to be used as CXCR4 antagonists. Four new C-functionalised bis-azamacrocycles that have an amino group to allow for subsequent conjugation were synthesised: 4-aminobenzyl-C-functionalised side-bridged bis-cyclam, 4-aminobenzyl-C-functionalised side-bridged bis-cyclam cyclen, 4-aminobenzyl-C-functionalised bis-cyclam and 4-aminobenzyl-C-functionalised bis-cyclam cyclen. Zinc(II), nickel(II) and copper(II) complexes of the 4-nitrobenzyl-C-functionalised side-bridged bis-cyclam were synthesised and characterised as CXCR4 antagonists. A selection of the synthesised compounds was biologically evaluated in a number of assays (displacement assays, anti-HIV assays, cytotoxicity assays and calcium(II) signalling assays) with the free ligands showing activity and the metal complexes also acxtive and significantly more potent.

Citation

Al-Zirgani, A. S. Z. (2015). Synthesis and characterisation of novel azamacrocyclic chelators for biomedical applications : biological activity and radiolabelling. (Thesis). University of Hull. Retrieved from https://hull-repository.worktribe.com/output/4224050

• Thesis Type: Thesis
• Deposit Date: Mar 24, 2022
• Publicly Available Date: Feb 24, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4224050
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: Jun 1, 2015