Synthesis and antitumor activity of a 2-hydroxy substituted chalcone (C6)

Abstract

Cancers account for approximately 13% of all deaths each year with breast cancer being one of the most common. Chemotherapeutic agents used in cancer usually have nonspecific toxicity which kills both tumor and normal cells and cause serious side effects that often limit their efficacy. This study aimed to synthesize chalcone and evaluate its antitumor activity.

Chalcone was synthesized using Claisen-Schmidt condensation and characterized using spectroscopic techniques. The LD₅₀ of the synthesized compound was estimated using OECD-425 guidelines in rats. A mammary tumor was induced with a single subcutaneous administration of 65 mg/kg of 1-methyl nitrosourea (MNU). The rats were palpated weekly to determine the size of the tumor. Eight weeks post MNU administration, the rats were divided into five groups of six rats each and treated with graded doses (12.5, 25, and 50 mg/kg) of the compound and paclitaxel (10 mg/kg) for six weeks. Before treatment, three rats were randomly selected and sacrificed, and mammary gland samples were subjected to histological assessment to confirm the induction of the tumor. At the end of the treatment, the rats were euthanized, and mammary glands were collected and subjected to histological evaluation. The possible mechanism of action of the synthesized compound was elucidated in silico using molecular docking.

The compound was synthesized and named C6. C6 was found to be relatively safe with LD₅₀ above 2000 mg/kg and exhibited remarkable antitumor activity. MNU-induced mammary tumor rats treated with C6 produced a significant decrease in tumor diameter when compared with the untreated group, histology slides displayed fewer signs of hyperplasia and small numbers of connective tissue with larger lobules when compared with the untreated group. In silico tubulin-binding interactions revealed that C6 binding to tubulin was like that of colchicine, and also has higher affinity to tubulin than colchicine. 

The synthesized chalcone demonstrated significant antitumor activities in MNU-induced mammary tumors in rats postulated via inhibition of tubulin polymerization.