VCOM Louisiana Research Day Program Book 2024

Biomedical Research: Section 2

Prince Anim Addo, MS student; Siva Murru, PhD; Atchmnaidu Siriki, PhD ULM 25 SYNTHESIS AND IN-VITRO BIOLOGICAL EVALUATION OF PYRAZOLE MOLECULAR HYBRIDS AS POTENTIAL ANTI-CANCER AGENTS FOR NON-SMALL CELL LUNG CANCER CELLS

Background: Cancer is known to be one of the leading cause of morbidity and mortality worldwide with lung cancer considered as the principal cause of cancer death. Among men and women in the USA, lung cancer death is very high compared to all the other types of cancer (breast, prostate, colorectal, skin, pancreatic, etc.) known. Non-small cell lung cancer (NSCLC) accounts for 85 – 90% of all lung cancers and comprises non-squamous carcinoma (i.e. adenocarcinoma, large-cell carcinoma and other cell types) and squamous cell carcinoma. NSCLC is often diagnosed at advanced stage and survival outcomes with traditional first-line chemotherapy regimens (e.g. platinum-based regimens such as pemetrexed plus cisplatin) are generally poor, with a relative survival rate of 5 years < 15%. The high therapeutic properties (anti-tumor, anti-inflammatory, antipyretic, anti-viral) of the pyrazolone compounds have encouraged organic chemists to synthesize many novel chemotherapeutic agents due to the basic components consisting of nitrogen heterocycles. Objective: Cancer cells are able to withstand adverse external conditions (hypoxia, nutrient deprivation, and reduced growth factors) through angiogenesis and anaerobic glycolysis. Majority of US-FDA approved cancer drugs

contain nitrogen heterocycles derivatives (bridged bicyclic, fused, macrocyclic) as the significant/basic structural component. Nitrogen-based heterocycles are prominent in natural (DNA, RNA) and synthetic compounds, playing an important role in biological systems with essential structure-activity relationships (SARs). Development of new drugs for the treatment of NSCLC has become necessary due to the emergence of cancer patients developing drug resistance to Tyrosine kinase inhibition (TKI) based drug regimens leading to treatment failure. There is a high unmet need for effective therapies for NSCLC harboring mutations in the cancer related genes that are associated with loss of efficacy or resistance to multiple therapeutic strategies. Our idea is to develop non-TKI anticancer agents (which has optimized reaction conditions, purification, solubility) that can be eventually developed for the treatment of resistant NSCLC. Methods: We have recently reported pyrazolones derivatives as potential anticancer molecules for NSCLC. Based on the preliminary anticancer activity data, we have designed and synthesized molecular hybrids based on C-O and C-C bond formation using microwave assisted synthetic approaches. Microwave assisted methods played an important role

aiding the rapid expansion of small molecule compounds libraries during the drug discovery phase to identify potent candidate(s) with improved selectivity, potency, and sustainability. Our lab was able to design and synthesize varied set of 23 compounds using microwave assisted process which was confirmed using GC-MS, HRMS and NMR analysis techniques. In assessing the suitability of our synthesized compounds against NSCLC, we screened a total of 23 compound library series using MTT assay with seeded cells concentration of 1X 104 on cancerous A549 cells. Based on the screening results, we obtained 5 highly active compounds which were screened on non-cancerous HLF cells to assess its toxicity on a time/dose dependent activity of 24hrs, 48hrs and 72hrs respectively. Results: It is our aim to screen newly synthesized pyrazole molecular hybrids on non small cell lung cancer (A549 cell lines). Through microwave assisted processes, our lab was able to design and synthesize varied set of 23 compounds which was confirmed using GC MS, HRMS and NMR techniques. Additionally, we have performed ADMET predictions using SwissADME software to evaluate the drug potential of the synthesized compounds, considering physicochemical properties,

39 2024 Via Research Recognition Day