Synthesis And Biological Evaluation Of Several Natural Saponins And Analogues

Saponins, complex glycosides of triterpenes or steroids, are largely distributed in nature with significant pharmacological activities. They are the major biologically active ingredients in many Chinese traditional herbs. However, the structural diversity of saponins lies mainly in their "glycoforms", and the formidable task of isolating individual saponin from a plant species turns out to be a great obstacle for further pharmacological research. Chemical synthesis could remove this bottle-neck. This serves as a basis for revealing the relationship between structure and bioactivity.1. Synthesis and Biological Evaluation of Oleanane-type triterpenoid Saponins1) Synthesis of natural products scabiosaponins E-GScabiosaponins E-G, three new bidesmosidic oleanolic acid saponins, were isolated from Sacbiosa tschiliensis Grun. (Dipsacaceae), a perennial herb used for the treatment of headache, fever, cough, and jaundience in the northeast region of the Inner Mongolia autonomy district and the west of Hebei Province, and they showed remarkable inhibition activity against pancreatic lipase. Scabiosaponins E-G is a series of glycosides of oleanolic acid with one sugar chain being attached through an ether linkage at C-3, and another through an ester linkage at C-28 (a so-called "bidesmosidic saponin"). Because of its highly activities and unique chemical structure, Scabiosaponins E-G were chosen as our target molecules. With an effective synthetic access to the key intermediate employing the two sequential glycosylation steps, then we successfully synthesized the natural products Scabiosaponins E-G by adopting the one-pot sequential glycosylation strategy under the combined use of glycosyl trichloroacetimidates and p-toluene 1-thioglycosides (STol) as donors.2) Synthesis of Prosapogenin lb and its analoguesNikaido, T examined the biological activity of isolated compounds from Scabiosa tschiliensis, among of which prosapogenin 1b showed the stronged inhibitory activity against pancreatic lipase. The inhibitory activity of prosapogenin 1b against pancreatic lipase at 0.12 mg/mL was similar to that of orlistat at 0.005 mg/mL. Prosapogenin 1b and its analogues 2-56-2-63 were synthesized in a convergent approach. We employed an odourless 2-methyl-5-tert-butylphenyl(Mbp) thioglycoside and trichloroacetimidate donors in one-pot reaction as a key step. After removing the isopropylidene, the arabinopyranosyl residue adopted a 1C4 conformation instead of the typical 4C1 form. While all protecting group were removed, the arabinopyranosyl moiety returned to the normal 4C1 conformation.3) Synthesis of p-Hederin and its analoguesβ-Hederin, namely oleanolic acid 3-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside, is a oleanane-type triterpenoid saponin widely distributed in the nature. Sashida, Y., Lee, K., and Balansard, G. suggested thatβ-Hederin has prominent cytotoxicity to various human tumor cell lines such as HL-60, M4 Beu, A549, DLD1, PA1, PC3, etc. After examining structure-activity relationships, they observed that the sugar sequence O-α-L-rhamnopyranosyl-(1→)-α-L-arabinopyranoside at C-3 induces strong cytotoxicity and might be identified as a basic sequence for antitumor activity of oleanolic acid monodesmosides. Based on these complements. we designed and synthesizedβ-Hederin analogues 2-104-2-108 for structure-activity relationships investigation and development of desirable antitumor agents. 4) Biological evaluation of oleanane-type triterpenoid saponinsThe synthesized triterpenoid saponins Scarbiosaponins E-G, Prosapogenin 1b, 2-56-2-63,β-Hederin,2-104-2-112 were evaluated for their inhibitory activity against pancreatic lipase and cytotoxic acticities against three human cancer cell lines (HL-60, A549, A375). All the compounds showed remarkable inhibitory activity toward pancreatic lipase with the inhibition of 75%-100%. The compounds with no the sugar sequence O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside at C-3 were completely inactive toward HL-60. The free carboxylic acid groups in position 28 within their chemical structures were required for enhancement of pancreatic lipase inhibition and antitumor activities against HL-60, A549, and A375.2. Synthesis of marine steroids Linckosides analoguesNeurotrophic factors (NTFs) have been considered as good candidates for prevention and treatment of neurodegenerative diseases. Since such endogenous factors are too large in size to pass through the blood-brain barrier, exogenous low-molecular-weight compounds that mimic the activity of NTFs might be developed as promising therapeutic drugs to treat various neurodegenerative diseases.Marine steroids linckosides, were isolated from the Okinawan starfish Linckia laevigata, which represent a series of new steroid glycosides. These compounds are not only potent inducers of neurite outgrowth on PC12 cells but also significant enhancers of nerve growth factor (NGF) to induce the neurite outgrowth. However, The isolation of each individual steroid from the starfish species presents a formidable task. Chemical synthesis of active analogous compounds is one of the useful strategies to screen out new low toxic and high effective medicine for treating neurodegenerative diseases. In this thesis, some steroid linckosides were synthesized with effective synthetic strategy. This serves as a basis of screening out lead medical compounds.