An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucl...An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucleotides and oligonucleotides, and were prepared in high yields of 81% to 91%. Alkyl modified aptamer AS1411s were synthesized using this method and the biological activity screening results demonstrated that alkylation at the 1^st P-S site on yielded stronger target protein binding capacity, greater growth suppression effects against K562 and HL-60 cell lines, and improved serum stability, as compared with AS1411. This modified aptamer may be useful in tumor detection and treatment.展开更多
RNA interference has been widely used for gene therapy of various infectious diseases and malignant tumors. However, its poor stability in serum has limited further clinic application. Here, we found that stability of...RNA interference has been widely used for gene therapy of various infectious diseases and malignant tumors. However, its poor stability in serum has limited further clinic application. Here, we found that stability of siRNA in serum enhanced obviously when 3′-terminus of sense strand （siRNA-pS） was conjugated with peptide, while same conjugation at 3′-terminus of antisense strand brought no such effects. And it was also found that only the peptide residue in siRNA-pS could be cut off by RNase A. All these results indicated that nucleases in serum prefer to invade siRNA duplex through the 3′-end of sense strand.展开更多
3-Deazaneplanocin A （3-DNPA, 2）, an antiviral and antitumor agent, has been synthesized in an optimized procedure in 10 steps, with an increased overall yield of 11.2%. Started from 2,4-dihyroxyl-3-nitropyridine, re...3-Deazaneplanocin A （3-DNPA, 2）, an antiviral and antitumor agent, has been synthesized in an optimized procedure in 10 steps, with an increased overall yield of 11.2%. Started from 2,4-dihyroxyl-3-nitropyridine, reduction of nitro group and ring closure of imidazole were carried out in one pot, without the separation of diaminopyridine （10）, to give 3-deazapurine （11）. Moreover, the conversion of 6-chloro-3-deazapurine （12） to 6-amino-3-deazapurine （13） and the synthesis of N^6,N^6,N9-tris-Boc-3- deazadenine （16） was promoted by microwave-aid method. Compound 16 benefited the formation of N9 isomer of 3-DNPA in Mitsunobu reaction.展开更多
To improve the stability and pharmacokinetic properties,prodrugs of L-ddG（L-2＇,3＇-dideoxy-guanosine）and L-D4G （L-2＇,3＇-dihydro-2＇,3＇-dideoxyguanosine）modified with a series of substituted amino groups at C-6...To improve the stability and pharmacokinetic properties,prodrugs of L-ddG（L-2＇,3＇-dideoxy-guanosine）and L-D4G （L-2＇,3＇-dihydro-2＇,3＇-dideoxyguanosine）modified with a series of substituted amino groups at C-6 position of the purine base were designed and synthesized and their anti-HIV activities were evaluated.Compounds 7d and 8g exhibited moderate activity and showed EC_（50）of 42μmol/L and 55μmol/L,respectively.展开更多
Advances in Science and Technology in the past few decades have led to a significant expansion of our knowledge about human health and disease. Today, there have never been such great needs for multidisciplinary resea...Advances in Science and Technology in the past few decades have led to a significant expansion of our knowledge about human health and disease. Today, there have never been such great needs for multidisciplinary researchers to come together and address the complex challenges in human health. State Key Laboratory of Natural and Biomimetic Drugs （SKLNBD） in Peking University, is one of the first state key laboratories established in China.展开更多
C-di-GMP is one kind of second messengers which plays an important role not only in the regulation of various bacterial physiological activities but also in the activation of innate immune response to induce typeⅠint...C-di-GMP is one kind of second messengers which plays an important role not only in the regulation of various bacterial physiological activities but also in the activation of innate immune response to induce typeⅠinterferon in mammalian cells.In this assay,by using one-pot phosphoramidite method,three novel kinds of analogs of c-di-GMP including its phosphorthiates modified by ganciclovir(7 a,7 b,7 c)have been designed and synthesized.The immune-stimulatory results of these c-di-GMP analogs in RAW-Lucia ISG cells indicated that they couldn’t induce the release of typeⅠinterferon,which demonstrated that the intact structure of ribose moieties is very vital for their bioactivity upon the activation of STING signaling pathway.展开更多
基金the Ministry of Science and Technology of China(Grant No.2012CB720604)National Natural Science Foundation of China(Grant No.21332010)
文摘An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucleotides and oligonucleotides, and were prepared in high yields of 81% to 91%. Alkyl modified aptamer AS1411s were synthesized using this method and the biological activity screening results demonstrated that alkylation at the 1^st P-S site on yielded stronger target protein binding capacity, greater growth suppression effects against K562 and HL-60 cell lines, and improved serum stability, as compared with AS1411. This modified aptamer may be useful in tumor detection and treatment.
基金Ministry of Science and Technology of China(Grant No.2012CB720604)National Natural Science Foundation of China(Grant No.20932001)
文摘RNA interference has been widely used for gene therapy of various infectious diseases and malignant tumors. However, its poor stability in serum has limited further clinic application. Here, we found that stability of siRNA in serum enhanced obviously when 3′-terminus of sense strand （siRNA-pS） was conjugated with peptide, while same conjugation at 3′-terminus of antisense strand brought no such effects. And it was also found that only the peptide residue in siRNA-pS could be cut off by RNase A. All these results indicated that nucleases in serum prefer to invade siRNA duplex through the 3′-end of sense strand.
基金National Natural Science Foundation of China (Grant No.20472006 and 20832008)
文摘3-Deazaneplanocin A （3-DNPA, 2）, an antiviral and antitumor agent, has been synthesized in an optimized procedure in 10 steps, with an increased overall yield of 11.2%. Started from 2,4-dihyroxyl-3-nitropyridine, reduction of nitro group and ring closure of imidazole were carried out in one pot, without the separation of diaminopyridine （10）, to give 3-deazapurine （11）. Moreover, the conversion of 6-chloro-3-deazapurine （12） to 6-amino-3-deazapurine （13） and the synthesis of N^6,N^6,N9-tris-Boc-3- deazadenine （16） was promoted by microwave-aid method. Compound 16 benefited the formation of N9 isomer of 3-DNPA in Mitsunobu reaction.
基金National Natural Science Foundation of China (Grant No.20472006 and 20832001)
文摘To improve the stability and pharmacokinetic properties,prodrugs of L-ddG（L-2＇,3＇-dideoxy-guanosine）and L-D4G （L-2＇,3＇-dihydro-2＇,3＇-dideoxyguanosine）modified with a series of substituted amino groups at C-6 position of the purine base were designed and synthesized and their anti-HIV activities were evaluated.Compounds 7d and 8g exhibited moderate activity and showed EC_（50）of 42μmol/L and 55μmol/L,respectively.
文摘Advances in Science and Technology in the past few decades have led to a significant expansion of our knowledge about human health and disease. Today, there have never been such great needs for multidisciplinary researchers to come together and address the complex challenges in human health. State Key Laboratory of Natural and Biomimetic Drugs （SKLNBD） in Peking University, is one of the first state key laboratories established in China.
基金National Natural Science Foundation of China(Grant No.U1604285,21572013)
文摘C-di-GMP is one kind of second messengers which plays an important role not only in the regulation of various bacterial physiological activities but also in the activation of innate immune response to induce typeⅠinterferon in mammalian cells.In this assay,by using one-pot phosphoramidite method,three novel kinds of analogs of c-di-GMP including its phosphorthiates modified by ganciclovir(7 a,7 b,7 c)have been designed and synthesized.The immune-stimulatory results of these c-di-GMP analogs in RAW-Lucia ISG cells indicated that they couldn’t induce the release of typeⅠinterferon,which demonstrated that the intact structure of ribose moieties is very vital for their bioactivity upon the activation of STING signaling pathway.
