Synthesis and in vivo studies of metformin analogues for management of impaired metabolic syndrome in pancreatic ductal adenocarcinoma
Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer that remains incurable because it is often detected at an advanced stage, making treatment difficult.
MARTIALS AND METHODS: The reaction of free metformin (5) with isothiocyanate derivatives (6-9) and the or with 4-toluenesulfonyl isocyanate (10) afforded the targeted metformin analogues (11-15). The in vitro anticancer impact of these compounds was assessed using cell lines of BJ1, PACA2, and HePG2.
RESULTS: Compound 13 had significant cytotoxic effects against PACA2 and HePG2 with mortality 88.30% and 71.20%, respectively. In a chronic study, the body weights of male rats receiving 13 at a dose of 50 mg/kg for 12 consecutive weeks showed an insignificant difference in the percentage change in body weight. Histopathological examination of the pancreas and liver with 13 exhibited normal histological structure of exocrine and endocrine parts. Additionally, normal cardiac myocytes were observed in the heart of rats treated with 13.
CONCLUSIONS: It can be inferred that the daily administration of 50 mg/kg of compound 13 over a duration of 12 weeks did not elicit any substantial alterations in body weight, biochemical, hematological, or histopathological parameters, while concurrently exhibiting pronounced anticancer efficacy against pancreatic ductal adenocarcinoma (PDAC).
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