Synthesis of aroyl thiophene C-nucleoside analogues

【作者】 周祥； 高飞； 梁岩； 张福义；

【Author】 Xiang Zou;Fei Gao;Yan Liang;Fuyi Zhang;The College of Chemistry and Molecular Engineering,The Key Lab of Chemical Biology and Organic Chemistry,Zhengzhou University;

【机构】 郑州大学化学与分子工程学院；

【摘要】 C-nucleoside and their analogues with heterocycle moiety directly attached to the carbohydrate through a C-C bond,different from the usual N-nucleosides or O-glycosides,result in better stability to both acidic and enzymatic hydrolysis.1 Most of them exhibit interesting biological activities.2 Aryl groups and aryl substituted heterocycles are frequently used as designed nucleobase surrogates to synthesize C-nucleoside due to their biological activities.These aryl groups can selectively form pairs with the same or other hydrophobic nucleobases in oligonucleotide duplexes due to the increased propensity to p-stacking and favorable desolvation energy compared to canonical hydrophilic nucleobases.Therefore,they have been used to explore base stacking in DNA–DNA duplexes and the molecular interactions in DNA–protein recognition processes.3 Thiophene is an important five-membered S-heterocycle and is considered as a privileged structure for combinatorial drug discovery.Many thiophene containing compounds possess protein inhibition and anticancer activities.Amongst these thiophene derivatives,the Cnucleosides analogues bearing thiophene as the surogate of the nucleobase are particularly interesting.Thiophenfurin4 as an antitumor agent is one of the examples.It can inhibit the growth of K562 human erythroid leukaemia and LoVo human colon adenocarcinoma,and exhibits substantial activity in vivo against L1210 leukaemia.Thiophenfurin also possesses good selectivity towards tumour cells in vitro and high-level of conversion to its dinucleotide form.Although the parent thiophene are easily prepared,the thiophene C-nucleoside analogues that the thiophene and sugar is linked through C-C bond are considerably more challenging.We have developed a concise synthesis of novel aroyl thiophene C-nucleoside analogues by the reaction of various terminal sugar alkynes with substituted benzoyl chlorides and 1,4-dithane-2,5-diol,followed by treatment with dilute HCl in one pot（scheme 1）.The sugar alkynes include structurally diversified pyranosides,furanosides,and acyclic sugar.The benzoyl chloride has various substituents such as NO₂,F,Cl,Br,OCH₃,CH₃.The synthetic method is general,mild and concise,and 32 examples have been given.The corresponding products are given in moderate to excellent yields.更多还原

【Abstract】 C-nucleoside and their analogues with heterocycle moiety directly attached to the carbohydrate through a C-C bond,different from the usual N-nucleosides or O-glycosides,result in better stability to both acidic and enzymatic hydrolysis.1 Most of them exhibit interesting biological activities.2 Aryl groups and aryl substituted heterocycles are frequently used as designed nucleobase surrogates to synthesize C-nucleoside due to their biological activities.These aryl groups can selectively form pairs with the same or other hydrophobic nucleobases in oligonucleotide duplexes due to the increased propensity to p-stacking and favorable desolvation energy compared to canonical hydrophilic nucleobases.Therefore,they have been used to explore base stacking in DNA–DNA duplexes and the molecular interactions in DNA–protein recognition processes.3 Thiophene is an important five-membered S-heterocycle and is considered as a privileged structure for combinatorial drug discovery.Many thiophene containing compounds possess protein inhibition and anticancer activities.Amongst these thiophene derivatives,the Cnucleosides analogues bearing thiophene as the surogate of the nucleobase are particularly interesting.Thiophenfurin4 as an antitumor agent is one of the examples.It can inhibit the growth of K562 human erythroid leukaemia and LoVo human colon adenocarcinoma,and exhibits substantial activity in vivo against L1210 leukaemia.Thiophenfurin also possesses good selectivity towards tumour cells in vitro and high-level of conversion to its dinucleotide form.Although the parent thiophene are easily prepared,the thiophene C-nucleoside analogues that the thiophene and sugar is linked through C-C bond are considerably more challenging.We have developed a concise synthesis of novel aroyl thiophene C-nucleoside analogues by the reaction of various terminal sugar alkynes with substituted benzoyl chlorides and 1,4-dithane-2,5-diol,followed by treatment with dilute HCl in one pot（scheme 1）.The sugar alkynes include structurally diversified pyranosides,furanosides,and acyclic sugar.The benzoyl chloride has various substituents such as NO₂,F,Cl,Br,OCH₃,CH₃.The synthetic method is general,mild and concise,and 32 examples have been given.The corresponding products are given in moderate to excellent yields.更多还原