Synthesis And Bioactivity Screening Of Lupeol And Novel Betulin Derivatives

Lupeol is a pentacyclic triterpene found in various fruits, vegetables andmedicinal plants. It has been shown to exhibit various pharmacological activitiesincluding beneficial activity against inflammation, cancer, arthritis, diabetes, heartdiseases, renal toxicity and hepatictoxicity, among which the antiproliferative effectagainst cancer cells from various tissue resources is most attractive. However, thecontent of lupeol in fruits, vegetables and medicinal plants is very low while thepresent synthetic methods for it are limited by high cost, long synthetic routs or rigidreaction conditions. Development of cost-effective approaches to the synthesis oflupeol is of great significance.Betulin is a lupane-type pentacyclic triterpene rich in plants. The content ofbetulin in the outer bark of white birches trees is high up to35%, which makes betulinreadily accessible. Synthesis and screening of novel bioactive pentacyclic triterpenefrom betulin has become one of the hot topics in medicinal chemistry.This work mainly includes the following three parts:1. Lupeol was prepared from betulin by a five-step synthetic route. Firstly, betulinwas peracetylated with acetic anhydride in anhydrous pyridine to afford betulin3-O,28-O-diacetate, which was selectively deacetylated at the C-28position to give3-O-acetylbetulin. Iodination of3-O-acetylbetulin with I2-PPh3-imidazole systemfollowed by deiodination with Zn-AcOH afforded lupeol acetate. Fially, lupeol wasobtained by deactylation of lupeol acetate. The main advantages of this approachinclude low cost of the starting material and other reagents, the short synthetic rout andthe relatively high yield (34%for5steps). It is a practical synthetic method whichcould provide an abundant resource for lupeol. In addition, lupeol was obtained byselectively tosylation of betulin at C-28position followed by reduction the tosylatewith NaBH4.2. Betulinal and28-iodo-3-acetoxylupeol were prepared from betulin and wereseparately used as precursors for derivation. Thiosemicarbazone and benzimidazolesmoieties were then introduced through nuclophilic substitution or condensation toobtain a series of new betulin derivatives.3. Anti-tumour activities of these betulin derivatives against nine tumor cell lineswere tested by MTT assay. Compound10and12demonstrated significant improvement on anti-tumour acivity as compared with betulin. IC50values ofcompound10against K562and U251is7.3and25.6μM respectively (193.6μM forbetulin), and compound12against K562and U251is2.2and2.4μM respectively(331.7μM for betulin).