Advances in chemistry and bioactivity of the genus Erythroxylum

Erythroxylum P.Browne is the largest and most representative genus of Erythroxylaceae family.It contains approxi-mately 230 species that are mainly distributed in tropical and subtropical regions.Some species in this genus,such as E.monogynum and E.coca,have been used as folk medicines in India or South America for a long history.It is well known that Erythroxylum plants are rich in tropane alkaloids,and the representative member cocaine shows remarka-ble activity in human central nervous system.However,many other types of active compounds have also been found in Erythroxylum along with the broadening and deepening of phytochemical research.To date,a total of 383 com-pounds from Erythroxylum have been reported,among which only 186 tropane alkaloids have been reviewed in 2010.In this review,we summarized all remained 197 compounds characterized from 53 Erythroxylum species from 1960 to 2021,which include diterpenes,triterpenes,alkaloids,flavonoids,and other derivates,providing a comprehensive overview of phytoconstituents profile of Erythroxylum plants.In addition,the biological activities of representative phytochemicals and crude extracts were also highlighted.

Identification and characterization of camptothecin tailoring enzymes in Nothapodytes tomentosa

Camptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity.Given that two C-10 modified camptothecin derivatives,topotecan and irinotecan,have been approved as potent anticancer agents,there is a critical need for methods to access other aromatic ringfunctionalized congeners(e.g.,C-9,C-10,etc.).However,contemporary methods for chemical oxidation are generally harsh and low-yielding when applied to the camptothecin scaffold,thereby limiting the development of modified derivatives.Reported herein,we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa,via metabolomic and transcriptomic analysis.These consist of a cytochrome P450(Nt CPT9H)which catalyzes the regioselective oxidation of camptothecin to 9-hydroxycamptothecin,as well as two methyltransferases(Nt OMT1/2,converting 9-hydroxycamptothecin to 9-methoxycamptothecin),and a uridine diphosphate-glycosyltransferase(Nt UGT5,decorating 9-hydroxycamptothecin to9-β-D-glucosyloxycamptothecin).Importantly,the critical residues that contribute to the specific catalytic activity of Nt CPT9H have been elucidated through molecular docking and mutagenesis experiments.This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering.This will hasten the discovery of novel C-9 modified camptothecin derivatives,with profound implications for pharmaceutical manufacture.