Chemical Constituents And Bioactivities Of Cephalotaxus Lanceolata K. M. Feng

The genus Cephalotaxus (Cephalotaxaceae), evergreen trees of southernAsia, has long been known to contain antileukemic ester alkaloids harringtonineand its congeners. So far, intensive investigations on discovering antitumorCephalotaxus alkaloids have attracted particular attention. Cephalotaxuslanceolata, mainly native to the mountains of Yunnan, is a member of the genusCephalotaxus. In folk medicine, this plant is used to expel parasites and foodstagnancy, moisten lung and stop cough.In this dissertation, we investigated the chemical constituents of thebranches and leaves of Cephalotaxus lanceolata K. M. Feng and their cytotoxicactivities.60compounds were isolated from the branches and leaves ofCephalotaxus lanceolata by column chromatograph over silica gel, SephadexLH-20, and octadecylsilyl (ODS), and53compounds were identified as followsby spectral techniques, including MS,1D-and2D-NMR, as well as single crystalX-Ray diffraction.1. Cephalanceolatine A (1)*2. Cephalanceolatine B (2)*3. Cephalanceolatine C (3)*4. Cephalanceolatine D (4)**5. Cephalotaxine (5)6. Epicephalotaxine (6)7. Cephalotaxine-N-oxide (7)8. Cephalotaxine β-N-oxide (8)9. Drupacine (9)10. Cephalotaxinone (10)11. Cephalotaxinamide (11)12.4-Hydroxycephalotaxine (12)13. Harringtonine (13)14. Homoharringtonine (14)15.2,7-Octadienoic acid (15)△16.7-Octenoic acid (16)△17. Oleuropeic acid (17)△ 18.1,2-Propanediol (18)△19.9-Hydroxy-4,7-megastigmadien-3-one (19)△20. Lanceoloside A (20)*21. Corchoionol C (21)△22.9,10-Dihydroxy-4,7-megastigmadien-3-one (22)△23.5,12-Epoxy-9-hydroxy-7-megastigmen-3-one (23)△24. Drummondol (24)△25. Lanceoloside B (25)**26. Lanceoloside C (26)**27. Loliolide (27)△28.(3S,5R,8S)-5,8-epoxy-6-megastigmene-3,9-diol (28)△29. Clovandiol (29)△30. Lanceolatin A (30)*31. Imbricatolic acid (31)△32.14-Dien-18-oic acid (32)△33. Dehydroabietic acid (33)△34.15-Hydroxydehydroabietic acid (34)△35. Lanceolatin B (35)*36. Lanceolatin C (36)*37. Lanceolatin D (37)*38. Lanceolatin E (38)*39. Lanceolatin F (39)*40. Hainanolide (40)41. Gongshanolide (41)*42. Taiwanhomoflavone-B (42)43. Taiwanhomoflavone-A (43)44.(7’S,8’R)-Dihydrodehydrodiconiferyl alcohol (44)△45.()-Isolariciresinol (45)△46. Lanceolatol (46)*47. p-Coumaric acid (47)△48. Junipediol A (48)49. Junipediol B (49)50. p-Hydroxybenzoic acid (50)△51.4-Hydroxy-3-methoxybenzoic acid (51)△ 52. Daucosterol (52)△53. β-Sitosterol (53)Among these isolates, compounds1、2、4、20、30、35、36、37、38、39、41、46were identified to be new compounds; Compounds3、25、26were new naturalproducts; Compounds15、16、17、18、19、21、22、23、24、25、26、27、28、29、31、32、33、34、44、45、47、50、51、52were isolated from this genus for thefirst time, and all compounds were isolated from Cephalotaxus lanceolata for the firsttime.All alkaloids were evaluated for their cytotoxic potential according to establishedprotocols. New alkaloids exhibited no cytotoxicity against HL-60. Compound5exhibited weak cytotoxicity against HCT116with IC50values of22.65μg/mL, whilecompound9demonstrated weak inhibition against A549with IC50values of28.29μg/mL, and moderate inhibition against HCT116and HepG2cell lines with IC50valuesof2.61and3.95μg/mL, respectively. Compound13showed strong cytotoxicity againstA549, HCT116, HepG2with IC50values of0.15,0.054,0.38μg/mL, respectively.Compound14also exhibited remarkable cytotoxicity against A549, HCT116, andHepG2with IC50values of0.085,0.001,0.087μg/mL, respectively, which was everstronger than DOX against HCT116. The cytotoxic alkaloids showed more potentcytotoxicity against HCT116than A549, SK-BR-3, and HepG2cell lines. Comparingthe relationship between the structures of1-14and their cytotoxcities, the ester sidechains at C(3) of cephalotaxine skeleton play the most important role in cytotoxicactivity of these alkaloids, and the composition of the side chain moiety can affect thecytotoxicity of alkaloid. In addition, the nitrogen lone pair of the cephalotaxine skeletonappeared to be also essential for its cytotoxicity. Furthermore, the ether linkage betweenC(2) to C(11), such as drupacine-type alkaloids, might also make some contribution tocytotoxicity. However, the dimeric alkaloids without ester side chain exhibited nocytotoxicity even if they possessed a drupacine-type unit. The influence of cardiacglycosides on the cycle of HCT116was also tested, and compounds13、14showedstrong S arret on it. Thus, their proliferation inhibition on HCT116may correspond tothe arrest of S phase. Compound40demonstrated weak inhibition against A549withIC50values of12.84μg/mL, and moderate inhibition against HCT116and HepG2celllines with IC50values of0.17and0.63μg/mL. In bioassay against LPS-induced NOproduction in RAW264.7macrophages, compounds35、36、37、38、39demonstratedmoderate activity at concentration of50μM.