Studies with tripterygium wilfordii : synthesis of diterpene analogues with potential pharmacological activity

• Main Author: Zetina-Rocha, Carlos B.
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/8471

This thesis is concerned with the development of synthetic routes leading to the preparation of a family of novel diterpenoid analogues structurally related to triptolide (1), an active constituent of the Chinese herbal plant Tripterygium wilfordii. The objective was to design a methodology which could allow access to a variety of potentially active analogues, which may contribute to a better understanding of the structure-activity relationship of this family of compounds by the evaluation of their pharmacological activity. In the first part of this research two alternative short syntheses to the phenolic diterpene isotriptophenolide (71) were developed, using the readily available dehydroabietic acid (60) as starting material. Subsequently, this ring C "activated" compound (71) was used as a key intermediate from which several synthetic pathways were derived, leading to the preparation of a number of new analogues possessing several unsaturated and oxygen functionalities in rings B and C of the molecule. These derivatives comprised quinoid-type compounds such as C8-methoxylated dienones (153) and the (7,8)a-epoxy-dienone, 72. Epoxidation of the latter compound produced two novel di-epoxidized analogues. A different synthetic sequence was also developed to the corresponding (7,8)P-epoxy-isomer (73), which upon epoxidation produced a di-epoxy compound. Another series of mono-epoxidized derivatives were obtained from the 8- hydroxy-dienones 157 and 158, prepared by changing the oxidation conditions of isotriptophenolide (71). Several alternative pathways were developed to some of the key synthetic intermediates and to the epoxy-dienones 72 and 73. In the later stages of this research, a new "unified" synthetic scheme was achieved which allowed the synthesis of the analogues 72, 73,157 and 158 (and consequently their corresponding epoxidized derivatives), in a remarkably short 1 to 3-step sequence. Also, a short series of biotransformation experiments was performed by incubating the epoxydienones 72 and 73 with TRP4a cell cultures, giving several ring-B oxygenated/unsaturated derivatives of isotriptophenolide (71). A total of 15 new quinoid/epoxy analogues, belonging to three main "series" of derivatives (i.e., 8-methoxy-, (7,8)epoxy-, and 8-hydroxy-dienones) were prepared in the present research. [Chemical models]