Synthesis of new indole derivatives as A2 adenosine receptor antagonists for the immunotherapy of cancer

Adenosine signalling mediated by G protein-coupled adenosine receptors (A1, A2A, A2B, and A3) is a key driver of tumor-associated immunosuppression, particularly under hypoxic conditions where extracellular adenosine accumulates. Among these receptors, A2A and A2B play central roles in suppressing anti-tumor immune responses and promoting tumor progression, making them attractive targets for cancer immunotherapy. This is especially relevant in pancreatic ductal adenocarcinoma (PDAC), a malignancy characterised by a highly immunosuppressive, adenosine-rich tumour microenvironment and limited response to current therapies. This PhD research focuses on the medicinal chemistry-led design, synthesis, and biological evaluation of a library of indole-based heterocyclic compounds intended as A2A/A2B adenosine receptor antagonists with potential anticancer activity. Multiple chemotypes were explored. The pyrazol[1,5-a]pyrimidine scaffold was prioritised using a modular synthetic strategy to investigate the biological effects of indole substitution patterns, N1-methylation, and incorporation of heteroaryl moieties such as furan, pyridine, and thiophene. Triazine-based analogues were developed in parallel as an alternative bis-indolyl framework to broaden chemical space and enable scaffold comparison. Biological evaluation was carried out in vitro using human PDAC cell lines (SUIT-028 and PaTu-T), with antiproliferative effects assessed via a 72-hour sulforhodamine B (SRB) assay. Screening identified several active compounds, predominantly within the pyrazole[1,5-a]pyrimidine series, which displayed clear concentration-dependent growth inhibition.