Quassinoids with Inhibitory Activities against Plant Fungal Pathogens from Picrasma javanica

Abstract

A bioactivity-guided study on the leaves of Picrasma javanica led to the isolation of 19 quassinoids, including 13 new compounds. The structures of the new compounds were elucidated by a combination of spectroscopic data analysis, X-ray crystallography studies, and electronic circular dichroism (ECD) data interpretation. Compounds 1−7 are rare examples of quassinoids with a keto carbonyl group at C-12. The biological activities of 11 of the more abundant isolates were evaluated against five phytopathogenic fungi in vitro, and several of them including 6 and 15 showed moderate inhibitory effects that were comparative to those of the positive control, carbendazim. In addition, the preliminary structure−activity relationships (SARs) of these quassinoids were also investigated.

Recent syntheses and biological profiling of quassinoids

“…Notably, 133 and 134 contain several stereocenters present in bruceantin (6), brusatol (7), and related quassinoids. The correct installation of the C-8 stereocenter is especially impressive as it is known to be quite challenging to establish.…”

“…To determine if the activity of these analogs originated from a release of brusatol (7), non-cleavable derivatives connected through an ether bond (236-239) were synthesized and shown to be generally inactive, indicating that the main function of the amino acid conjugates was to serve as prodrugs even though such conjugates may retain some intrinsic activity.…”

“…Attempts to synthesize amino acid conjugates at the C-15 position also resulted in the accidental formation of compound 240 through an intramolecular etherification reaction. Analog 240 was found to be inactive in Raji cells, demonstrating the importance of the C-15 side chain in brusatol (7). 53 In addition to the synthetic analogs, naturally occurring quassinoids have also been found to influence the PI3K/Akt/NF-κB signalling pathway.…”

“…Since their isolation and structural elucidation, quassinoids such as quassin (5) and brusatol (7) have been the subject of intensive biological and synthetic studies attributable to their potent biological properties. [3][4][5][6][7][8][9][10][11][12] For example, the quassinoid bruceantin (6) has reached phase II clinical trials for the treatment of metastatic breast cancer and malignant melanoma in 1982 and 1983, respectively. 13,14 Although originally dismissed for its toxic side effects, bruceantin still appears to sustain potential as a viable drug candidate for several cancer types.…”

“…Since their isolation and structural elucidation, quassinoids such as quassin ( 5 ) and brusatol ( 7 ) have been the subject of intensive biological and synthetic studies attributable to their potent biological properties. 3–12 For example, the quassinoid bruceantin ( 6 ) has reached phase II clinical trials for the treatment of metastatic breast cancer and malignant melanoma in 1982 and 1983, respectively. 13,14 Although originally dismissed for its toxic side effects, bruceantin still appears to sustain potential as a viable drug candidate for several cancer types.…”