Research

Topoisomerase II (Topo II) inhibitors constitute an important class of anticancer drugs. Current studies on the development of Topo II inhibitors have been largely hampered by the limited resource of new chemical scaffolds. Extremophilic enzymes and bioactive substances derived from extremophiles, which have developed special architecture and physiological functions in the long evolutionary process to survive in the extreme environment, have become the important resources for anticancer drug development.

Figure. The structure of Tricitrinol B(Image by SIMM)

Researchers from Dr. GENG Meiyu’s group,Shanghai Institute of Materia Medica(SIMM) and Dr. GU Qianqun’s laboratory, Ocean University of China have identified Tricitrinol B, a trimer of citrinin possessing novel structure, from fifteen citrinin derivatives isolated from Penicillium citrinum HGY1-5 and demonstrated its anticancer activity.

Tricitrinol B showed extensive cytotoxicity in 17 tumor cells with comparable low-micromolar IC50 values (1-10 μM) and potential anti-multidrug resistance capabilities. Mechanistically, Tricitrinol B acts as an intercalating topoisomerase IIα (Topo IIα) poison, which inhibits the enzyme activity of topo IIα by predominantly interfering with the Topo IIα-mediated poststrand-passage cleavage/religation equilibrium. The impaired Topo II catalytic cycle leads to DNA double-strand breaks, which further results in the G2/M arrest and apoptosis of tumor cells.

This work has importantly highlighted Tricitrinol B as a novel class of Topo IIα-inhibitory skeletons for developing new chemotherapeutic agents.

The work, supported by National Science & Technology Major Project“Key New Drug Creation and Manufacturing Program”, the National Natural Science Foundation of China and Program of Shanghai Subject Chief Scientist, has been published on the Journal of Medicinal Chemistry (2011, 54：5796-5810).