Introduction: Throughout history, natural products (NPs) have provided a rich source of compounds that have wide applications in the fields of medicine, health sciences, pharmacy and biology. Although naturally active substances are good lead compounds for the discovery of new drugs, most of them suffer from various deficiencies or shortcomings, such as complex structures, poor stability and solubility. Therefore, structural modification of NPs is needed to develop novel compounds with specific properties. Areas covered: This article presents an overview on the structural modifications of NPs in drug development. The application of multiple classes of NPs to the treatment of conditions such as cancers, infection, Alzheimer’s and diabetes are discussed. This article also reveals that modification of NPs is a versatile approach to explore their mode of actions, which may lead to the discovery of novel drugs. Expert opinion: NPs are usually described by structural diversity and complexity. The use of isolated NPs as scaffolds for modification is a good approach to drug discovery and development. Despite many limitations associated with NPs, the total synthesis, semisynthetic modification, SAR-based modification, sometimes even a single atom alteration, may lead to the discovery of a novel drug.

The vital roles of microtubule in mitosis and cell division make it an attractive target for antitumor therapy. Colchicine binding site of tubulin is one of the most important pockets that have been focused on to design tubulin-destabilizing agents. Over the past few years, a large number of colchicine binding site inhibitors (CBSIs) have been developed inspired by natural products or synthetic origins, and many moieties frequently used in these CBSIs are structurally in common. In this review, we will classify the CBSIs into classical CBSIs and nonclassical CBSIs according to their spatial conformations and binding modes with tubulin, and highlight the privileged structures from these CBSIs in the development of tubulin inhibitors targeting the colchicine binding site.

Cystathionine β-synthase (CBS) is responsible for the first enzymatic reaction in the transsulfuration pathway of sulfur amino acids. The molecular function and mechanism of CBS as well as that of transsulfuration pathway remain ill-defined in cell proliferation and death. In the present study, we designed, synthesized and obtained a bioactive inhibitor CH004 for human CBS, which functions in vitro and in vivo. CH004 inhibits CBS activity, elevated the cellular homocysteine and suppressed the production of hydrogen sulfide in a dose-dependent manner in cells or in vivo. Chemical or genetic inhibition of CBS demonstrates that endogenous CBS is closely coupled with cell proliferation and cell cycle. Moreover, CH004 substantially retarded in vivo tumor growth in a xenograft mice model of liver cancer. Importantly, inhibition of CBS triggers ferroptosis in hepatocellular carcinoma. Overall, the study provides several clues for studying the interplays amongst transsulfuration pathway, ferroptosis and liver cancer.