Synthesis and biological evaluation of natural quinone chalcones and unnatural analogues / Shelly Gapil Tiamas @ Edwin

• Main Author: Shelly Gapil , Tiamas @ Edwin
• Format: Thesis
• Published: 2023
• Subjects: Q Science (General); QD Chemistry
• Online Access: http://studentsrepo.um.edu.my/15053/1/Shelly_.pdf; http://studentsrepo.um.edu.my/15053/2/Shelly.pdf; http://studentsrepo.um.edu.my/15053/

Apoptosis is a type of programmed cell death that multicellular organisms to regulate tissue homeostasis through the elimination of useless or potentially harmful cells. The key players of apoptosis are caspases, a family of protease whose activation is induced by two major signalling pathways, extrinsic and intrinsic pathways. One of these main apoptotic pathways is regulated by proteins from Bcl-2 family (the intrinsic pathway). Numerous studies in recent years have shown that anti-apoptotic Bcl-2, Bcl-xL and Mcl-1 protein overexpression is involved in the developments of anticancer therapies, leading to the development of new anticancer drugs. The feasibility of disrupting protein-protein interactions between anti- and pro-apoptotic members of the Bcl-2 family proteins, using a small molecule inhibitor has been demonstrated. As a result, Venetoclax was the first to be approved by the FDA in 2016 as an inhibitor of antiapoptotic proteins. In the past decades, tremendous efforts have been made to isolate novel natural products, from microbes, plants, and other living organisms, to assess their anticancer properties and to explore the mechanism of action. It is estimated that between 1981 and 2019, approximately 25% of all newly approved anti-cancer drugs were related to natural products. Screening of plants extract, marine organism or microorganism can provide highly original and functional bioactive molecules that are unlikely obtained by screening synthetic libraries. Thus, our objective is to develop new compounds, derived from plants, that restore apoptosis by targeting proteins of Bcl-2 family. The phytochemical study of Fissistigma latifolium, a Malaysian Annonaceae, led to the isolation of new prenylated chalcones with good affinity for anti-apoptotic proteins. Based on these promising results, a bioinspired total synthesis of the natural compounds isolated in our laboratory was developed in a diastereoselective fashion. Indeed, the cyclohexene core was built by a key Diels-Alder cycloaddition inspired by the biosynthesis of these prenylated chalcones. Then, the two enantiomers of fislatifolic acid and fislatifolione were prepared with a good overall yield and a complete diastereoselective. The evaluation on anti-apoptotic proteins revealed that one enantiomer of (+)-acid fislatifolic is a good inhibitor of Bcl-xL and Bcl-2 proteins on a micromolar range. Surprisingly, the (+)-Weinreb amide intermediate had a promising activity on Mcl-1 and Bcl-2. This led us to elaborate more than 20 amide analogues and evaluation on the anti-apoptotic proteins.