Guggulsterone - a potent bioactive phytosteroid: synthesis, structural modification, and its improved bioactivities

Abstract

Guggulsterone is a phytosteroid derived from the oleo-gum resin of the critically endangered plant Commiphora wightii. This molecule has attracted increasing attention due to its excellent biochemistry potential and the compound has consequently been evaluated in clinical trials. With a low concentration in natural resources but wide medicinal and therapeutic value, chemists have developed several synthetic routes for guggulsterone starting from various steroid precursors. Moreover, numerous studies have attempted to modify its structure to improve the biological properties. Nowadays, green and sustainable chemistry has also attracted more attention for advanced chemical processes and reactions in steroid chemistry. The present review aimed to summarize the literature and provide an update about the improvements in the chemical synthesis and structural modification of guggulsterone from the view of green chemistry. Moreover, this review encompasses the improved activities of structurally modified guggulsterone derivatives. We expect that the information provided here will be useful to researchers working in this field and on this molecule.

Fig. 1. Representative examples of biologically active phytosteroids isolated from various plants.

Fig. 2. Crystal diagram of (E)-guggulsterone reported by Sarkhel and co-workers.

Fig. 3. Structures of starting materials for guggulsterone synthesis.

Fig. 4. First synthetic route for (E/Z)-guggulsterone, (a) Benn and Dodson's method, (b) alternative method and (c) rearrangement mechanism.

Fig. 5. Improved methods for guggulsterone, (a) Pratap and co-worker's method and (b) Gokaraju and co-worker's method.

Fig. 6. Shortest fabrication routes for guggulsterone, (a) Ham and co-worker's method and (b) Gioiello and co-worker's method.

Fig. 7. Chin and co-workers' synthesis of guggulsterone from natural steroids, (a) androstenedione and (b) androstenolone.

Fig. 8. Chin and co-workers' synthesis of guggulsterone from natural precursors, (a) androstenolone and (b) testosterone.

Fig. 9. Reddy and co-workers' formal synthesis of guggulsterone.

Fig. 10. Advantages of green chemistry processes over conventional chemistry synthesis.

Fig. 11. Structural modification sites of guggulsterone.

Fig. 12. Lee and co-workers' method for the synthesis of (E)-guggulsterone-triazole derivatives.

Fig. 13. Kohyama and co-workers' designed method for obtaining guggulsterone derivatives via A- and D-ring modification.

Fig. 14. Lee and co-workers' method for the synthesis of (E)-guggulsterone-triazole derivatives.

Fig. 15. Kohyama, and co-workers' method for synthesizing enone-deficient guggulsterone derivatives.

Fig. 16. Kohyama and co-workers' method for synthesizing gem-difluoroalkene guggulsterone derivatives.

Fig. 17. Feng and Zhang's method for obtaining the 18-norsteroid derivative.

Fig. 18. Kovacs and co-workers' green catalytic system for obtaining steroidal-oxadiazole derivatives.

Fig. 19. Guggulsterone citations that appear along the time line from 1972 till 2023. The Pubmed database was searched by the use of “guggulsterone” as a keyword. The plot shows the cumulative number of hits identified for each year after the first report of guggulsterone.