Studies On The Synthesis Of 6,7-seco-ent-kauranes And The Synthesis And Antitumor Activity Of Allogibberellin Hybrids

ent-Kaurane diterpenoids are distributed in Isodon?Lamiaceae?,Compositae,Livewort,Euphorbiaceae,Pteridaceae and other plants.It is an important part of the diterpenoid family.In the past thirty years,over 1000 ent-Kaurane diterpenoids were isolated and identified from genus Isodon.Many of them possess antibacterial,antitumor,anti-inflammatory,antiviral,antimalaria and other biological activities.The 6,7-seco-ent-kauranes can be regarded as the oxidative cleavage products of the C-6-C-7 bond of 7,20-epoxy-ent-kauranes.They are mainly classified into two subgroups:spiro-lactone?7,20-lactone?and enmein type?1,7-lactone?.Due to the interesting bioactivities and unique molecular structure of such compounds,it is of great significance to synthesize these diterpenes and their analogues efficiently.The thesis is divided into five chapters.In the first chapter,the sources,classifications,bioactivities,biosynthetic pathway and chemical synthesis of ent-kaurane diterpenoid were summarized.In the second chapter,the synthetic methods towards Neolaxiflorin B of spiro-lactone type 6,7-seco-ent-kauranes diterpenoid were studied.Using 2-methyl-3-butyn-2-ol as starting material,the Pauson-Khand reaction as the key step,compound2-1-45 was synthesized in four step reactions.Applying 1,3-cyclohexanedione as starting material,the palladium catalyzed cyclization as the key step,compound 2-1-3 was prepared in seven steps.The key intermediate 2-1-66 was obtained by Michael addition followed by selective deoxygenation.?Scheme 1?In the third chapter,the synthetic methods for 6,20,15?-trihydroxy-6,7-seco-1?,7-olide-ent-kaur-16-ene of enmein type 6,7-seco-ent-kauranes diterpenoid were investigated.Utilizing 1,4-cyclohexanediol as starting material,the radical cyclization as the key step,compound 3-1-54 was synthesized in seven step reactions.Applying isobutyraldehyde as starting material,the Robinson cyclization as the key step,compound3-1-95 was obtained in three steps.The key intermediate 3-1-109 was obtained in four step reactions.This synthetic method lays the foundation towards the synthesis of such compounds and their analogues.?Scheme 2?In the fourth chapter,A series of novel alligibberic 1,2,3-triazole hybrids were designed and synthesized.Their biological activities were evaluated in vitro against five human tumor cell lines.The hybrids 3-5-32-3-5-47 bearing?,?-unsaturated ketone moiety exhibited excellent in vitro cytotoxicity.Compounds 3-5-32-3-5-39 were more sensitive to MCF-7 cell lines while the hybrids 3-5-40-3-5-47 were more selective to SW480 cell lines,with IC₅₀ values at least 4 to 20-fold more cytotoxic than Cisplatin?DDP?.Compounds 3-5-45,3-5-46 and 3-5-47 have broad spectrum of anticancer activities.Mechanism of action studies indicated that compound 3-5-47 can cause the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.In the fifth chapter,the experiment procedure and spectrum data of some compounds from chapter 2 to chapter 4 were recorded.