Synthesis of flavonoids nitrogen mustard derivatives

Study on their antitumor activity in vitro

Significance 

Flavonoids are secondary metabolites of polyphenols and are found in leguminous plants. They possess a wide range of biological activities such as anti-inflammatory, antioxidant, antibacterial, antidiabetic, anti-osteoporosis, antiangiogenic and anticancer effects. The anticancer activity of flavonoids is related to their modulation of signal transduction pathways within cancer cells. As a result, flavonoids can inhibit cell proliferation, angiogenesis, and metastasis, while also promoting apoptosis. The general classes of flavonoids include isoflavones, flavones, flavonols, flavanones, anthocyanins, and chalcones. Many favorable properties have made them of interest to medicinal chemists. For example, Dihydroxyflavones that contain the ortho-dihydroxy group have strong antioxidant properties. Genistein which is a highly abundant soy isoflavone possess striking structural similarity to 17β-oestradiol which explains its inhibition on estrogen-dependent cancer. In addition, genistein has also been reported to inhibit the proliferation of human lung cancer cell line by suppressing lipid synthesis. Another study has also suggested that genistein has the ability to prevent prostate cancer growth by inhibiting telomerase activity. Chrysin, another flavonoid can suppress cell proliferation and cause cell apoptosis making it a potential anticancer agent. Chrysin has also been found to prevent tumor cells from expressing the hypoxia-inducible factor-1α.

Nitrogen mustards such as cyclophosphamide, chlorambucil and melphalan are used in clinical practice as DNA alkylating agents. They bind to DNA and cross-link the two chains thereby preventing DNA replication. However, drug resistance and the fact that they are highly toxic to normal cells with numerous side effects have limited their cancer treatment. To address these issues, scientists have tried to develop anticancer agents with dual target by combining nitrogen mustards with other agents. Some of these combinations have shown promising potential.

In a new study, researchers from the College of Chemistry at Beijing Normal University: Xi Yan, Jinglei Song, Meixuan Yu and Hao-Ling Sun together with Haijun Hao from   Beijing University of Chemical Technology evaluated the cyotoxic activities of chrysin and genistein nitrogen mustard derivatives and studied the potential mechanisms by which they inhibit cell proliferation. They successfully demonstrated that the synthesized compounds had potent anti-cancer activity. The research study is published in the Journal of Bioorganic Chemistry.

The research team developed and synthesized for the first time never reported novel series of chrysin and genistein nitrogen mustard derivatives. They carefully evaluated the activity of these compounds in preventing cell proliferation against a variety of human cancer cell lines: A549, DU145, HeLa, HepG2, MCF7, PC-3 and SH-SY5Y. They found that most of their compounds exhibited better antiproliferative activity against the seven cancer cell lines than melphalan and raw materials. In addition, some of the compounds had IC50 values that were lower than that of melphalan. One of their molecules, they designed it by Compound 8b was identified as the most promising. It exhibited antitumor activity against the seven cancer cell lines with IC50 values that were lower than that of melphalan. Compound 8b was also found to induce cell death in HeLa cells and this was attributed to the arrest of cell cycle at G2/M phase mediated by mitochondrial membrane potential loss.

Through synthesis of novel molecules and performing in vitro studies, the authors successfully been able to demonstrate that compound 8b is a potential anticancer agent. This will serve as a foundation for future pre-clinical and possibly clinical studies.

Reference

Yan X, Song J, Yu M, Sun HL, Hao H. Synthesis of flavonoids nitrogen mustard derivatives and study on their antitumor activity in vitro. Bioorg Chem. 2020 Mar;96:103613.

Go To Bioorg Chem

About Priti