| A total of 171 compounds,including 6 new skeletons,63 new compounds,and 102 known compounds,were isolated from three medicinal plants,namely Zephyranthes candida,Zephyranthes carinata,and Mallotus esquirolii.The structures were identified by spectroscopic analyses,NMR calculation,electronic circular dichroism(ECD)calculation,as well as single crystal X-ray diffraction using Cu Kαradiation.Some compounds were evaluated for their anti-tumor activities,anti-acetylcholinesterase(AChE)inhibitory activities,and anti-inflammation.In addition,the anti-tumor mechanism and the binding sites with acetylcholinesterase of some compounds were also studied.Z.candida,also called as ’ganfengcao’ and ’conglan’ in China,belonging to the family Amaryllidaceae,is native to South America,and widely cultured as an ornamental.The whole plants of Z.candida are used as a traditional Chinese medicine in China to treat infantile convulsions,epilepsy,and tetanus.The chemical constituents of Z.candida were studied leading to the isolation of 60 compounds including 3 new skeletons and 30 new compounds.The isolated compounds comprised 56 alkaloids,including 3 new skeletons(1-3)and 27 new alkaloids(4-30),and 4 flavans,including 3 new flavans(57-59).As far as we know,zephycandidines Ⅰ(1)and Ⅲ(3)represent the first examples of 7-phenyl-hexahydroindole and 5,2’-dimethyl-biphenyl-2-ylamine alkaloids,respectively.Zephycandidine Ⅱ(2)is the first C3a-phenyl-hexahydroindole type alkaloid isolated from the genus of Zephyranthes.Compounds 36-37,49,51-53,and 55-56 were isolated from the genus of Zephyranthes for the first time.Compounds 31-35 and 44 were isolated from the species of Z.candida for the first time.In addition,these 60 compounds were evaluated for their AChE inhibitory activities as well as their structure-activity-relationships.Compounds 3,28,and 30 showed significant AChE inhibitory activities(IC50<10 μM).Meanwhile,the docking studies of 1-4 and galantamine with AChE revealed that interactions with W286 and Y337 are necessary for the AChE inhibitory activity.The anti-tumor activities of some compounds were also evaluated.The result declared that zephycandidine A(1)exhibited significant cytotoxicity against five cancer cell lines,which is much better that that of the positive control cisplatin,with selectivity indices as high as 10 when compared to the normal Beas-2B cell.Further studies suggested that zephycandidine A(1)induces apoptosis in leukemia cells by the activation of caspase-3,upregulation of Bax,downregulation of Bcl-2,and degradation of PARP expression.In addition,the anti-inflammatory activities of these 60 compounds were also evaluated and new conpounds 15 and 18 showed potential anti-inflammatory activities(IC50<10 μM).Z.carinata,previously known as Z.grandiflora,also called as ’saifanhonghua’and ’fengyulan’ in China,belong to the family Amaryllidaceae.The whole plants of Z.carinata are used to treat falls swelling,snake bites,and vomiting bleed as a traditional Chinese medicine in China.Previous phytochemical studies on Z.carinata have focused on the bulbs,however,there are no any reports of chemical constituents of Z.carinata collected in China as well as the phytochemical studies on the whole plants of Z.carinata.Thus,the chemical constituents of the whole plant of Z.carinata were studied leading to the isolation of 70 compounds including 60 alkaloids(2 new skeletons(61-62)and 16 new alkaloids(63-78)and 10 non-alkaloids(121-130).Zephycarinatine A(61)represents the first example of an Amaryllidaceae alkaloid framework type bearing an acetyl functionality at C-4a in typical Amaryllidaceae dinitrogenous alkaloids.Zephycarinatine B(62)is the first example of a de-aldehyde-secoplicamine alkaloid framework.The absolute configurations of the N-oxide in lycorine-type alkaloids were established for the first time by single crystal X-ray diffraction using Cu Ka radiation.It is also the first time to report the montanine-type alkaloids in the genus of Zephyranthes.In addition,some of the isolated compounds were also evaluated for their anti-AChE activities,anti-tumor activities,and anti-inflammatory activities.The new compounds 76 and 77 showed significant AChE inhibitory activities(IC50<10μM).Mallotus esquirolii(Euphorbiaceae)are widely distributed in Guangxi,Guizhou,Hainan,and Yunnan provinces of China.However,the chemical constituents and biological activities of M.esquirolii have never been reported.It is the first time to study the chemical constituents of the twigs and leaves of M.esquirolii leading to the isolation of 41 compounds including 3 new skeletons and 14 new compounds.The isolated compounds comprised 9 maytansinoids,including 3 new skeletons(131-133)and 3 new compounds(134-136),and 32 non-alkaloids,including 11 new phenolics(137-147).Mallonoids A-C(131-133)are the first representatives of seco-maytansinoid-type skeleton bearing a 6/6/6/5 cyclic system containing an unprecedented 2,6-dioxa-4-azabicyclo[3.3.1]nonan motif.The new phenolic enantiomers 137 and 138 were achieved by chiral resolution via chiral HPLC using a Chiralpak IC column.The absolute configurations of 137 and 138 were confirmed by ECD calculation.It is the first time to report the single-crystal X-ray diffraction data of naturally occurring maytansinoids.Thus,the absolute configurations of naturally occurring maytansinoids can be further evidenced.Some of the isolated compounds were also evaluated for their anti-inflammatory activities and anti-tumor activities against five human cancer cell lines.The result showed that compounds 131-139,146,and 148-150 exhibited significant cytotoxicity against five cancer cell lines with selectivity indices as high as 1000.Meanwhile,compounds 132,134-136,and 148-150 showed more potent cytotoxicity than one of the positive controls(cis-platin).In addition,the new phenolics 139 and 146 can selectively inhibit HL-60 cell lines. |
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