Photo of research team

Podophyllotoxin is widely used in pharmaceuticals, such as cathartic and antirheumatic active ingredients used as antiviral drugs and cancer treatment. In pharmaceutical chemistry technology, podophyllotoxin is a precursor of three anti-cancer drugs such as etoposide, teniposide and etoposide phosphate, which have strong cytotoxic activity and few side effects. Some studies on podophyllotoxin analogues such as 4-aza-podophyllotoxin have been synthesized and shown to have anti-cancer activity according to the tubulin inhibition mechanism similar to podophyllotoxin. Derivatives of 4-azapodophyllotoxin are known to be potent inhibitors of DNA topoisomerase II/ or tubulin, and have recently attracted the attention of researchers.

Thiourea compounds are one of the more established special structures in medicinal chemistry. Some drugs and compounds containing the thiore group exhibit therapeutic and pharmacological biological activities such as antiviral, anticonvulsant, anti-inflammatory, antibacterial and anti-tumor effects. Furthermore, thiores appear in many protein kinase inhibitors, demonstrating their ability to form hydrogen bonds in ATP. They also exhibit strong topoisomerase inhibitory activity, by inhibiting angiogenesis that nourishes cancer cells and directly inhibits tumor growth.

In order to access the properties of thiourea and podophyllotoxin groups, the research team of Dr. Nguyen Thi Thuy Hang of the Institute of Chemistry conducted: "Research on the synthesis and biological activity of new quinoline derivatives of podophyllotoxin" (code VAST04.07/20-21) with the goal of finding new compounds 4-aza podophyllotoxin which has outstanding chemical activity.

The research team has successfully synthesized 17 new quinoline compounds of podophyllotoxin, including 5 quinoline derivatives of podophyllotoxin, 12 new 5-thiourea-4-aza-2,3-didehydropodophyllotoxin derivatives, by multicomponent synthesis method under mild conditions and without the use of a catalyst. The research team provided spectral data obtained from NMR, MS or IR to confirm the structures of 17 newly synthesized substances.

Structures of the compounds 4-aza-2,3- didehydropodophyllotoxin and thiourea -aza-2,3- didehydropodophyllotoxin

Cytotoxicity screening results on in vitro models with 02 cell lines of liver cancer (HepG2) and breast cancer (MCF7) of 17 newly synthesized substances showed that the new thiourea-4-aza-2, 3-didehydropodophyllotoxin shows good cancer cytotoxic activity by inhibiting the growth rate of this cell for both cancer cell lines at a threshold of ≤10 μM, much stronger than other common compounds 4-aza-2,3-didehydropodophyllotoxin. Furthermore, through comparison of the obtained activity with the structural correlation of the substance group, scientists have discovered that the change in chemical properties and bulkiness of Cα substituents of the thiourea group has an influence on the activity of derivatives.

Dr. Hang and his colleagues have built a process to synthesize 17 clean substances on a laboratory scale and conducted molecular docking simulations of newly synthesized substances. At the same time, scientists have provided theoretical analyzes on the influence of structure, chemical groups, bulkiness or position of groups on the activity of derivatives and confirmed the correlation on molecular docking model. Molecular docking studies also showed that the tested molecules had high binding affinity for beta topoisomerase II, consistent with the results of activity tests on in vitro models of two cancer cell lines MCF7 and HepG2.

The research results were published in 01 international article in the Journal of Heterocylic chemistry and 01 domestic article published in Vietnam Journal of Science and Technology and were graded B by the Acceptance Council of VAST. From the achieved successes, Dr. Hang wishes to continue researching and developing new thiore compounds in future projects to create many new compounds with scientific significance and applications to support and treat diseases in medicine.

Translated by Tuyet Nhung
Link to Vietnamese version