| Cancer has become a serious threat to mankind’s health and life because of its high fatality rate and gradually increasing morbidity.The high-risk behaviours of chemotherapeutic agents limit their clinical application.As the main bioactive constituents of Panax ginseng,ginsenosides have been reported to have anti-tumour effects.During our previous work,two active dammarane-type natural compounds,namely,25-OH-PPD and 25-OCH3-PPD were obtained from the the leaves of P.Ginseng.Studies demonstrated that they could inhibit tumor cell proliferation,induce apoptosis and influence the associated proteins expression.They exhibited stronger bioactivities with 10-fold to 100-fold increases relative to the marketed agent ginsenoside-Rg3.What’s more,they also had no significant toxicity to the normal cells compared with the severe side effects of chemotherapy.Based on the previous work,we modifided the lead compounds(25-OH-PPD and 25-OCH3-PPD)in order to find new compounds with higher antitumor activities and lower toxicity.By physico-chemical data and spectral methods(1H NMR,13C NMR,HSQC,HMBC and HR-ESI-MS),three types of compounds(a total of sixty-three)were identified as:nine chloroacetyl derivatives:3β,12β-O-di-chloracetyl-dammar-20(21)-ene-25-ol(1),12β-O-chloracetyl-dammar-20(21)-ene-3β,25-diol(2),3β,25-O-di-chloracetyl-dammar20(22)-ene-12β-ol(3),3β,12β-O-di-chloracetyl-dammar-20(22)-ene-25-ol(4),12β-0chloracetyl-dammar-20(22)-ene-3β,25-diol(5),(20R)-3β,12β-O-di-chloracetyl-dammarane20,25-diol(6),(20R)-3β,25-O-di-chloracetyl-dammarane-12β,20-diol(7),(20R)-3β-Ochloracetyl-dammarane-12β,20,25-triol(8),(20R)-12β-O-chloracetyl-dammarane-3β,20,25-triol(9)。Ten amino aicd derivatives:(20R)3β,12β-O-di-(Boc-L-leucyl)-dammarane-20,25-diol(1z),(20R)-3β-O-(Boc-L-leucyl)-dammarane-12β,20,25-triol(1x),(20R)-3β-O-(L-leucyl)dammarane-12β,20,25-triol(lxt),(20R)-3β,12β-O-di-[Boc-L-glutamoyl(OBzl)]-dammarane-20,25-diol(2z),(20R)-3β-O-[Boc-L-glutamoyl(OBzl)]-dammarane-12β,20,25-triol(2x),(20R)-3β-O-(L-glutamoyl)-dammarane-12β,20,25-triol(2xt),(20R)-3β-O-(Boc-L-isoleucyl)dammarane-12β,20,25-triol(3x),(20R)-3β-O-(L-isoleucyl)-dammarane-12β,20,25-triol(3xt),(20R)-3β-O-(L-arginyl)-dammarane-12β,20,25-triol(4xt),(20R)-12β-O-(L-alanyl)dammarane-3β,20,25-triol(5yt).Forty-four benzoyl derivatives:(20R)-25-methoxy-dammarane-12β,20-diol-3β-ylbenzoate(1a),(20R)-25-methoxy-ammarane-20-ol-3β,12β-diyl-benzoate(1b),(20R)-25methoxy-dammarane-3β,20-diol-12β-yl-benzoate(1c),(20R)-25-methoxy-dammarane12β,20-diol-3β-yl-4’-nitrobenzoate(2a),(20R)-25-methoxy-dammarane-20-ol-3β,12β-diyl-4’nitrobenzoate(2b),(20R)-25-methoxy-dammarane-3β,20-diol-12β-yl-4’-nitrobenzoate(2c),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-3’,5’-dinitrobenzoate(3a),(20R)-25methoxy-dammarane-20-ol-3β,12β-diyl-3’,5’-dinitrobenzoate(3b),(20R)-25-methoxydammarane-3β,20-diol-12β-yl-3’,5 ’-dinitrobenzoate(3c),(20R)-2 5-methoxy-dammarane-12β,20-diol-3β-yl-4’-bromobenzoate(4a),(20R)-25-methoxy-dammarane-20-ol-3β,1 2β-diyl-4’bromobenzoate(4b),(20R)-25-methoxy-dammarane-3β,20-diol-12β-yl-4’-bromobenzoate(4c),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-4’-iodobenzoate(5a),(20R)-25methoxy-dammarane-20-ol-3β,12β-diyl-4’-iodobenzoate(5b),(20R)-25-methoxy-dammarane-3β,20-diol-12β-yl-4’-iodobenzoate(5c),(20R)-25-methoxy-dammarane-12β,20-diol-3βyl-cinnamate(6a),(20R)-25-methoxy-dammarane-20-ol-3β,12β-diyl-cinnamate(6b),(20R)-25-methoxy-dammarane-3β,20-diol-12β-yl-cinnamate(6c),(20R)-25-methoxydammarane-12β,20-diol-3β-yl-4’-fluorocinnamate(7a),(20R)-25-methoxy-dammarane-20-ol3β,1 2β-diyl-4’-fluorocinnamate(7b),(20R)-25-methoxy-dammarane-3β,20-diol-12βyl-4’-fluorocinnamate(7c),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl2’-iodobenzoate(8a),(20R)-25-methoxy-dammarane-20-ol-3β,12β-diyl-2’-iodoobenzoate(8b),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-2’-chloro-5’-iodobenzoate(9a),(20R)-25-methoxy-dammarane-20-ol-3β,12β-diyl-2’-chloro-5’-iodobenzoate(9b),(20R)-25methoxy-dammarane-12β,20-diol-3β-yl-4’-Ghlorocinnamate(10a),(20R)-25-methoxydammarane-20-ol-3β,12β-diyl-4’-chlorocinnamate(10b),(20R)-25-methoxy-dammarane3β,20-diol-12β-yl-4’-chlorocinnamate(10c),(20R)-25-methoxy-dammarane-12β,20diol-3β-yl-2’-nitrobenzoate(11a),(20R)-25-methoxy-dammarane-20-ol-3β,12β-diyl-2’nitrobenzoate(11b),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-4’-chlorobenzoate(12a),(20R)-25-methoxy-dammarane-20-ol-3β,12β-diyl-4’-chlorobenzoate(12b),(20R)-25methoxy-dammarane-12β,20-diol-3β-yl-2’-bromo-5’-fluorobenzoate(13a),(20R)-25methoxy-dammarane-20-ol-3β,12β-diyl-2’-bromo-5 ’-fluorobenzoate(13b),(20R)-25methoxy-dammarane-12β,20-diol-3β-yl-2’,4’-difluorobenzoate(14a),(20R)-25-methoxydammarane-20-ol-3β,12β-diyl-2’,4’-difluorobenzoate(14b),(20R)-25-methoxydammarane-12β,20-diol-3β-yl-3’,5 ’-dimethylbenzoate(15a),(20R)-25-methoxydammarane-20-ol-3β,12β-diyl-3’,5’-dimethylbenzoate(15b),(20R)-25-methoxy-dammarane1 2β,20-diol-3β-yl-2’-methylbenzoate(16a),(20R)-25-methoxy-dammarane-3β,20-diol-12β-yl-2’-methylbenzoate(16c),(20R)-25-methoxy-dammarane-12β,20-diol3β-yl-2’-chlorobenzoate(17a),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-3’fluorobenzoate(18a),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-3’-methylbenzoate(19a),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-3’,5’-dibromobenzoate(20a),(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-4’-fluorobenzoate(21a).The derivatives were preliminarily screened for their inhibitory activities against human tumor cell lines.Results showed that chloroacetyl derivatives(1,3 and 4),amino aicd derivatives(2xt and 4xt)and benzoyl derivatives(3a,11a,14a and 18a)exhibited stronger antiproliferative activities.The antitumor mechanis of the compound 4xt against DU 145 cells were detected by morphological analysis and flow cytometry.The results indicated that compound 4xt could induce apoptosis.Structure-activity relationships showed that for the chloroacetyl derivatives,the carbon-carbon double bond at the C-20 position played an important role in improving the antiproliferative activity.On the basis of the double bond,the more substituent groups yielded the better bioactivity.For the amino aicd derivatives,compounds with amino acids(hydrophilic substituents)at the C-3 position were more active than correspondent those with N-Boc-amino acids,suggesting that the exposure of the polar group(such as amino group)could increase the inhibitory activities.For the benzoyl derivatives,the introduction of aromatic groups at C-3 increased the bioactivities,while the groups at C-12 decresased the bioactivities.The same substituents at meta-position and ortho-position of aromatic benzene had stronger antitumor effects compared to the ones at para-position.This research provided novel ideas and theoretical references for the exploration of new antiproliferative agents with high efficiency and low toxicity. |
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