Total Synthesis and Anticancer Activity of Novel <i>Pulsatilla</i> Saponin D Analogues

Abstract

Novel saponins that retain a free carboxyl group at the C-17 position and various sugars linked at the C-3 position of hederagenin aglycone were synthesized via stereospecific glycosylation. Since these natural products represented by Pulsatilla saponin D (PSD) were obtained in very small amounts, the total synthesis developed in this paper will resolve this problem of scarcity. The two types of synthesized arabinose-and rhamnose-cored saponins showed potent anticancer activity against a human lung cancer cell line (A549), and most disaccharide moiety saponins possessed more potent anti-lung cancer activity. Among the novel PSD analogues containing disaccharide saponins, compound 10i showed anti-lung cancer activity (6.6 µM) that was four-fold more potent than the clinical agent Iressa ® (26.08 µM). Key wordskalopanaxsaponin A, and sapindoside C have been shown to have potent cytotoxic activities toward various cancer cell lines.2-7) Among hederagenins, Pulsatilla saponin D (PSD) 10 ( Fig. 1) not only displayed strong in vitro anticancer activities, but also more potent in vivo antitumor activities in mice bearing Lewis lung carcinoma, exceeding the effects of even taxol and doxorubicin.8) In addition, we reported total synthesis of Pulsatilla saponin D (PSD). 9) These natural saponin products were obtained in small amounts, which was a limiting factor. Chemical synthesis may resolve this problem, and may easily provide suitable compounds for study of structure-activity relationships (SAR) and for the other studies.2,10) The result of SAR showed saponins with hederagenin retaining the free carboxyl group at the C-17 position had stronger anticancer activity than related compounds with other substituents. The hederagenin derivatives, that have sugar moieties on the C-3 position, also showed potent anticancer activity.11,12) Most isolated PSD analogs maintained derivative with sugars bound at the 2-OH of the arabinose moiety.8) Therefore, we proposed to study the effect of derivatization at 3-OH on the anticancer activity for SAR study. In this paper, we report total synthesis of new PSD analogs with various sugar moieties linked at C-3 position of hederagenin and at 3-OH of arabinose moiety. We also evaluated the in vitro anticancer activity of these new compounds. Results and DiscussionWe designed two types of saponin analogues arabinose-and rhamnose-directly glycosylated hederagenins. Stereospecific glycosylation of the glycosyl acceptor, as illustrated by the arabinose moiety 1, with perbenzoylated trichloroacetimidates donors 1a-d [13][14][15][16] was achieved in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) in dichloromethan (CH 2 Cl 2 ) at −78°C to give disaccharides 2a-d (Chart 1). Then, the acetyl group was removed using acetyl chloride/ CH 3 OH to give compounds 3a-d. 17) Glycosylation of compounds 1a-d with the C-4 free hydroxyl group of compounds 3a-d under the TMSOTf as a promoter at −78°C afforded trisaccharide 4a-g. The hydroxyl groups at the C-3, -4 positions in compound 6 as t...

Platelet-Membrane-Camouflaged Black Phosphorus Quantum Dots Enhance Anticancer Effect Mediated by Apoptosis and Autophagy

“…H6, derived from HED, may improve the antitumor action of paclitaxel . HED saponins (such as macranthoside B), triterpene saponin compound 8, and Pulsatilla saponin D analog (compound 10i) exhibit antitumor effects. − It was indicated that the sugar structures (i.e., α-hederin) of triterpenoid saponins are closely related to their anticancer properties . HED and its analogs have potential anticancer effects; however, the efficiency of HED is poor, with the underpinning anticancer mechanism remaining unclear.…”

Pulsatilla chinensis (Bge.) Regel: A Systematic Review on Anticancer of Its Pharmacological Properties, Clinical Researches and Pharmacokinetic Studies

“…At present, the existing literature shows that PC saponins can make glycolysis key proteins ERK1/2, hypoxia-inducible factor-1α (HIF-1a), Ras, glucose transporter 1 (GLUT1), lactate transporter (MCT4), Hexokinase 2 (HK2), MCT1, c-Myc and other factors were significantly reduced ( 91 ). The results showed that PC saponins can regulate the energy metabolism of tumor cells through the HIF-1α pathway to achieve the effect of inhibiting tumor growth ( 66 ).…”

Cytotoxicity, Hemolytic Toxicity, and Mechanism of Action of Pulsatilla Saponin D and Its Synthetic Derivatives

“…10 Novel analogues of 1, including some with various sugar moieties linked at the C-3 position of hederagenin, have been synthesized, but did not show improved cytotoxicity. 11 In recent years, our group has reported new triterpenoid saponins modified at the C-28 COOH substituent with amide, ester, or nitric oxide (NO) donating groups. Moreover, some derivatives exhibited dramatically decreased hemolytic toxicity accompanied by potent tumor growth inhibition against murine H22 hepatocellular cells in vivo.…”

“…Moreover, some derivatives exhibited dramatically decreased hemolytic toxicity accompanied by potent tumor growth inhibition against murine H22 hepatocellular cells in vivo. 12–15 In light of the above results, 11–15 new structure−activity relationship (SAR) correlations and structure−toxicity relationship (STR) correlations of 1 were explored in this report. First, new derivatives of 1 with a modified C ring were designed and synthesized (Scheme 1).…”

“…Considering the potent antitumor value and low natural yield of 1 , a practical synthesis in 17.4% overall yield from l -arabinose in eight steps was reported in 2013 . Novel analogues of 1 , including some with various sugar moieties linked at the C-3 position of hederagenin, have been synthesized, but did not show improved cytotoxicity . In recent years, our group has reported new triterpenoid saponins modified at the C-28 COOH substituent with amide, ester, or nitric oxide (NO) donating groups.…”