Semisynthesis and cytotoxicity evaluation of a series of ocotillol type saponins and aglycones from 20(S)-ginsenoside Rg2, Rh1, protopanaxatriol and their 20(R)-epimers

Abstract

With the oxidation treatment, eighteen compounds were separated from 20(S)-ginsenoside Rg 2 , Rh 1 , protopanaxatriol(PPT) and their 20(R)-epimers in total and cytotoxicity of most of them was evaluated against three human cancer cell lines HeLa, A549 and MCF-7 by 3-(4,5-dimetylthiazol-z-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Their structures were confirmed by means of nuclear magnetic resonance(NMR) and mass spectrometry and the results were compared with those of previous literature. In this study, we systematically semisynthesized all four ocotillol type saponins, i.e., (20S, 24S), (20S, 24R), (20R, 24S) and (20R, 24R). All the configurations at C20 kept the same with their starting materials. Meanwhile a pair of C24 epimers was generated in terms of ocotillol type saponins. In addition, seven compounds (4-8, 13 and 14) were reported firstly. The cytotoxic results distinguished the ocotillol type products (6, 7, 13 and 14) from 20(R)-PPT and 20(R)-ginsenoside Rh 1 , which possessed better cytotoxicities than their correspondents from 20(S)-epimers against HeLa cells, and the carbonyl group at C3 can improve the cytotoxicity, which helped us to gain deeper insight into Ocotillol type saponins.

Synthesis of Ocotillol-Type Ginsenosides

“…Then, removal of the benzoyl group under basic conditions afforded the intermediates 22a and 22b (98%). On the one hand, 22a and 22b were fully deprotected by desilylation with CSA and hydrogenolysis of the 4 benzyl groups, thus yielding 24­( R )-Rh2 epoxide ( 23a ) and its 24­( S )-isomer ( 23b ) (99% over 2 steps) . On the other hand, 22a and 22b were coupled with donor 7 under the promotion of Ph 3 PAuNTf 2 and provided 24a and 24b in high yield (>90%) and complete β-selectivity ensured by the benzoyl protecting group at the 2-position of the glucosyl donor.…”

“…However, no stereoselectivity was observed and the corresponding ocotillol-PPT was isolated in a moderate 55% yield and in a 1:1 mixture of cis/trans-THF ring. Thus, standard m -CPBA in CH 2 Cl 2 was employed and provided the corresponding ocotillol-PPT in a high 94% yield, albeit in an 1:1 mixture of 24­( R / S )-epimers, inseparable at this stage. Several functionalizations of the 25-OH were carried out in order to separate the two diastereoisomers.…”

“…After full deprotection, including desilylation, saponification of the 4 benzoyl groups, and hydrogenolysis of the 4 benzyl groups, gynoside B ( 25b ) and its 24­( R )-epimer ( 25a ) were isolated in 90% and 94% yields, respectively, over 3 steps. Gynoside B has also been named Rg3 oxide/epoxide or pseudoginsenoside GQ in the literatures. ,, It is worth mentioning that a stepwise glycosylation strategy was adopted in order to control the 1,2-trans configuration of the two glycosidic bonds, and that the NMR data of 23a / 23b and 25a / 25b were in agreement with those reported in the literature (Supporting Information). , …”

“…Gynoside B has also been named Rg3 oxide/epoxide or pseudoginsenoside GQ in the literatures. ,, It is worth mentioning that a stepwise glycosylation strategy was adopted in order to control the 1,2-trans configuration of the two glycosidic bonds, and that the NMR data of 23a / 23b and 25a / 25b were in agreement with those reported in the literature (Supporting Information). , …”

“…On the basis of this consideration, semisynthesis of ocotillol-type ginsenosides have been described by oxidation of the corresponding dammarane saponins. The oxidation is usually carried out with m -CPBA, H 2 O 2 , or oxone either on the natural or partially protected dammarane saponins . The cyclization then provides a 1:1 mixture of C-24 epimers while the configuration at the C-20 remains unchanged (Scheme , A).…”