Synthesis And Biological Testing Of The Target Antitumor Compounds Of Podophyllotoxin,Camptothecine And Erianin

An important approach of the discovery of antitumor durgs is the synthesis and structure modifications of active natural products. Podophyllotoxins, camptothecins and erianins, wide-spreaded in plants, are three kinds of antitumor natural products. In this thesis, the studies were carried out on them and consisted of three parts.This chapter summarized studies on bibenzyls from natural products. Their structure types, plant origin, total synthesis, structure modification and activities were introducted in detail. The author wished that this review could be helpful tu design and development of bibenzyls drugs.To obtain better the therapeutic agents with high activies and less toxic to natural cell, seven kinds derivatives of podophyllotoxin were designed, synthesized and evaluated for their biological activities in this chapter.(1) Based on biotin with better biological activity and good water-solubility in human body,14compouds were synthesized though associated podophyllotoxin and biotin with different the length of the linker. As the results, compound27(IC50=0.13-0.84μM) showed the highest activities, which has no linking apacer between the biotin and podophyllotoxin, and4’-OCH3group in the E ring.(2) Based on D-glucose as targeted anticancer chemotherapy and histone deacetylase and HDAC inhibitor has attracted much attention for the development of anticancer drugs,21compouds were synthesized via4β-triazole rings. As the results, compounds59(IC50=0.80-4.36μM), and65(IC50=0.59-2.9μM) exhibited higher activities. Cytotoxicities have been effect by the substituent on the glucose, perbutyrylated glucosides, the length of the linker and the substituent on the4’-position of the E-ring.(3) The chemical synthesis of a series of podophyllotoxin-glycosides of D-galactose, D-mannose, and D-xylose, and the bulky substituents at C-4and E ring was changed,22compouds were synthesized via4β-triazole rings. As the results, compound100(IC50=2.85-7.28μM), and113(IC50=0.67-7.41μM) shows strong anticancer activity.(4) The anticancer activity of other types of podophyllotoxin perbutyrylated glycosides of D-galactose, D-mannose, D-xylose, L-rhamnose, D-arabinose, maltose, and lactoose,40compouds were synthesized. As the results, most tagter compounds showed more effective superior or comparable cytotoxicities than VP-16. Compound144(IC50=0.49-6.70 μM),167(IC50=0.14-1.65μM),170(IC50=0.60-1.42μM) and180(IC50=0.61-1.69μM) show the highest potency of anticancer activity, is characterized by a perbutyrylated a-D(+)-galactosyl residue, no linking spacer between the sugar residue and the triazole ring, and a4’-OH group on the E ring.(5) ynthesis of16bisepipodophyllotoxin derivatives by Click reaction. Most of these compounds show weak cytotoxicity, the most active compound208(IC50=0.43-3.50μM), both having a β-perbutyrylated glucose residue and4’-OCH3group on the E ring, further proved4’-methylation of podophyllotoxin scaffold can significantly affect the potency of the anticancer activity.To obtain better the therapeutic agents with high activies and less toxic to natural cell, Based on20(s)-OH group is not necessary for biological activies, and biotin with better biological activity and good water-solubility in human body,12compouds were synthesized though associated camptothecin and biotin with different the length of the linker. As the results, compound3.34(IC50=0.34-1.85μM) which has the aminocaproic acid linking apacer between the biotin and camptothecin and10-OH group in the camptothecin scaffold, compound3.36(IC50=0.34-1.85μM) which has the aminocaproic acid linking apacer between the biotin and camptothecin and10-OH group and7-ethyl group in the camptothecin scaffold showed the highest potency.To obtain better the therapeutic agents with high activies, seven kinds derivatives of erianin were designed, synthesized and evaluated for their biological activities in this chapter.(1) Based on butanedioic acid and biotin with better biological activity and good water-solubility in human body,11compouds were synthesized though associated erianin and biotin with different the length of the linker. As the results, compound4.1.08(IC50=48-62nM) and4.1.11(IC50=26-30nM) showed the highest activity.(2) Based on glycosides and perbutyrylated glycosides with better biological activity,30glycosides of erianin were synthesized. As the results, perbutyrylated-D-arabinopyranoside4.2.1e (IC50=0.23-0.25μM), perbutyrylated-D-xylopyranoside4.2.1h (IC50=0:48-0.91μM), D-glucopyranooside4.2.4a (IC50=1.5-2.9μM) and D-mannopyranooside4.2.4c (IC50=1.7-2.8μM) showed the highest anticancer activies.