Design, synthesis, and anticancer activity of phenoxyacetohydrazide derivatives in burkitt lymphoma

Burkitt lymphoma (BL) is an aggressive non- Hodgkin lymphoma mainly driven by c- MYC translocations, leading to uncontrolled cell growth and high mortality. Although treatments have improved, issues like toxicity, resistance, and poor outcomes after recurrence remain major challenges. In this study, a series of phenoxyacetohydrazide derivatives were synthesized and characterized using spectroscopic techniques. Their anticancer activity was tested against Burkitt lymphoma cell lines. The compounds were evaluated for cytotoxicity at various concentrations, and the most effective ones were selected for further analysis. Structural modifications produced candidates that were screened for in-vitro cytotoxicity against BL cells (Blc), human lung adenocarcinoma (A549), and normal fibroblasts (NIH- 3 T 3) using trypan blue and MTT assays to determine IC50 values. Several compounds exhibited significant activity against cancer cells with lower toxicity toward normal cells. Lead compounds were then tested in a murine BL ascites model over 30 days, with survival rates and ascitic volume monitored. Compounds 12 d and 12 f were identified as the most active, killing Blc cells with IC 50 values of 11. 8 ± 0. 0.2 µM and 12. 3 ± 0. 1 µM, respectively, while showing minimal toxicity toward NIH- 3 T 3 cells (IC 50 > 40 µM). In vivo, 12 d and 12 f significantly increased median survival times and reduced malignant ascites by 67-72%, indicating strong suppression of tumor growth and related symptoms. Additionally, molecular docking was performed to predict the binding modes of the synthesized ligands with the Pygo- BCL 9 Wnt signaling complex (PDB ID: 2 vp 7: A), involved in decoding methylated histone H 3 tail, and Bruton' s Tyrosine Kinase (BTK) kinase domain (PDB ID: 3 pj 2). The docking results showed promising inhibitory activity of compounds 12 d and 12 f against these target proteins, suggesting their potential as anti- cancer agents. Overall, the findings demonstrate that chemical structure can be optimized for potency and tolerability, potentially overcoming challenges associated with conventional therapies.