To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate Cp...To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo.Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers,was conducted.Antibodies against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes.Four scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice.Adding anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor effect.When to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less pronounced.The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.展开更多
The a-L-rhamnopyranosyl phosphomonoesters conjugated with L-amino acid methyl esters were stereoselectively synthesized in a convenient route by utilizing H-phosphonate intermediate.
5,7-Dimethoxy-2-phenylquinolin-4-yl phenyloxy （N-L-alanine ethyl ester） phosphoramidate （C28H29N2O7P, Mr = 536.17） has been synthesized by a facial phosphorylated reaction, and its structure was determined by IR, ...5,7-Dimethoxy-2-phenylquinolin-4-yl phenyloxy （N-L-alanine ethyl ester） phosphoramidate （C28H29N2O7P, Mr = 536.17） has been synthesized by a facial phosphorylated reaction, and its structure was determined by IR, NMR, HR MS and X-ray single-crystal diffraction. The crystal belongs to triclinic, space group P1^-, with a = 11.375（2）, b = 11.591（2）, c = 11.638（2） A^°, α= 109.46（3）, β= 104.58（3）, γ= 100.48（3）°, V = 1339.6（5）A^°^3, Z = 2, Dc = 1.330 g/cm^3,μ = 0.152 mm^-1, F（000） = 564, the final R = 0.0654 and wR = 0.1546. In the crystal structure, the title compound is constructed by a centrosymmetric dimmer unit composed of a pair of π-π stacking diastereoisomers. The compound has a noteworthy feature in the framework, and such units are linked by two equal intermolecular P=O…H-N hydrogen bonds.展开更多
Novel steroidal phosphoramidate conjugates of 3＇-azido-2＇,3＇-dideoxythymidine （AZT） and amino acid esters were synthesized and determined by positive and negative ion electrospray ionization mass spectrometry. Th...Novel steroidal phosphoramidate conjugates of 3＇-azido-2＇,3＇-dideoxythymidine （AZT） and amino acid esters were synthesized and determined by positive and negative ion electrospray ionization mass spectrometry. The MS fragmentation behaviors of the steroidal phosphoramidate conjugates have been investigated in conjunction with tandem mass spectrometry of ESI-MS/MS. There were three characteristic fragment ions in the positive ion ESI mass spectra, which were the Na adduct ions with loss of steroidal moiety, amino acid ester moiety from pseudo molecular ion （M＋Na）^＋, and the phosphoamino acid methyl ester Na adduct ion by α-cleavage of the phosphora- midate respectively. The main fragment ions in negative ion ESI mass spectra were the ion （M-HN3）^-, the ion （M - AZT- H）^-, and the ion （M-steroidal moiety-H）^- besides the pseudo molecular ion （M-H）^-. The fragmentation patterns did not depend on the attached amino acid ester moiety.展开更多
Dinucleotide (TpAZT) phosphoramidates were synthesized by Todd reaction of dinucleoside H-phosphonates and amino acid methyl esters, and their diastereomers (Rp and Sp) were separated by crystallization, and the resul...Dinucleotide (TpAZT) phosphoramidates were synthesized by Todd reaction of dinucleoside H-phosphonates and amino acid methyl esters, and their diastereomers (Rp and Sp) were separated by crystallization, and the results showed that natural and cheap methyl esters of alanine and phenylalanine can be used for large-scale synthesis of dinucleotide analogs.展开更多
Two chiral phosporamidates, (R)-(–)-1, 1′-binaphthyl-2, 2′dihydroxy-N- [α-(S)-methylbenzyl] phosphoramidate and (–)-1,1′-biphenyl-2,2′-dihydroxy-N-[α-(S)-methylbenzyl]-phosphoramidate were synthesized. Their c...Two chiral phosporamidates, (R)-(–)-1, 1′-binaphthyl-2, 2′dihydroxy-N- [α-(S)-methylbenzyl] phosphoramidate and (–)-1,1′-biphenyl-2,2′-dihydroxy-N-[α-(S)-methylbenzyl]-phosphoramidate were synthesized. Their crystal structures were determined by X-ray single crystal diffraction analysis. The phosphoramidate molecules are self-associated by intermolecular NH ···O = P hydrogen bonds and aromatic edge to face interactions.展开更多
以三氯氧磷、1,3-丙二醇、N-羟乙基哌嗪为原料,合成了磷酰胺酯类化合物PN1,并利用PN1与氯磷酸二乙酯的亲核反应制备了磷酰胺酯类化合物PN2.采用核磁共振(nuclear magnetic resonance,NMR)1 H谱和13C谱、傅里叶变换红外光谱(Fourier tran...以三氯氧磷、1,3-丙二醇、N-羟乙基哌嗪为原料,合成了磷酰胺酯类化合物PN1,并利用PN1与氯磷酸二乙酯的亲核反应制备了磷酰胺酯类化合物PN2.采用核磁共振(nuclear magnetic resonance,NMR)1 H谱和13C谱、傅里叶变换红外光谱(Fourier transform infrared spectroscopy,FT-IR)、高分辨率质谱(high resolution mass spectroscopy,HRMS)表征了PN1和PN2的结构.采用二浸二轧的工艺,将不同质量分数(2%~27%)的PN1和PN2溶液应用于棉织物整理,研究其阻燃性能.经PN1整理后,棉织物的极限氧指数(LOI)从18%最高可提升至30.1%,在600℃时的成碳率从8%最高可上升至41.8%;经PN2整理后,棉织物的LOI从18%最高可提升至33.1%,在600℃时的成碳率从8%最高可上升至44.3%.展开更多
A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activitie...A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL biomarker for NSCLC） and human epidermal growth factor 2 （HER2, biomarker for breast cancer） with IC50 of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os （PO） administration of 6d in rat model （10 mg/kg） resulted in a moderate tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.展开更多
基金supported by the Russian Ministry of Science and High Education via the Institute of Cytology and Genetics (State Budget Project No.FWNR-2022-0016)the Russian Foundation for Basic Research (Grant No.18-29-09045).
文摘To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo.Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers,was conducted.Antibodies against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes.Four scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice.Adding anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor effect.When to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less pronounced.The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.
基金The authors would like to thank the financial supports from the NNSF of China(No.201 72033),the Ministry of Science and Technology,the Ministry of Education and Tsinghua University.
文摘The a-L-rhamnopyranosyl phosphomonoesters conjugated with L-amino acid methyl esters were stereoselectively synthesized in a convenient route by utilizing H-phosphonate intermediate.
基金supported by the National Natural Science Foundation of China (No. 20472076, 20572061, 20732004)Henan Academic Foundation of Science and Technology (No. 0512001400)
文摘5,7-Dimethoxy-2-phenylquinolin-4-yl phenyloxy （N-L-alanine ethyl ester） phosphoramidate （C28H29N2O7P, Mr = 536.17） has been synthesized by a facial phosphorylated reaction, and its structure was determined by IR, NMR, HR MS and X-ray single-crystal diffraction. The crystal belongs to triclinic, space group P1^-, with a = 11.375（2）, b = 11.591（2）, c = 11.638（2） A^°, α= 109.46（3）, β= 104.58（3）, γ= 100.48（3）°, V = 1339.6（5）A^°^3, Z = 2, Dc = 1.330 g/cm^3,μ = 0.152 mm^-1, F（000） = 564, the final R = 0.0654 and wR = 0.1546. In the crystal structure, the title compound is constructed by a centrosymmetric dimmer unit composed of a pair of π-π stacking diastereoisomers. The compound has a noteworthy feature in the framework, and such units are linked by two equal intermolecular P=O…H-N hydrogen bonds.
基金Project supported by the National Natural Science Foundation of China （No. 20542004）, the Specialized Research Fund for the Doctoral Program of Higher Education （No. 20050003104）, and the Beijing Commission of Education （No. XK 100030514）.
文摘Novel steroidal phosphoramidate conjugates of 3＇-azido-2＇,3＇-dideoxythymidine （AZT） and amino acid esters were synthesized and determined by positive and negative ion electrospray ionization mass spectrometry. The MS fragmentation behaviors of the steroidal phosphoramidate conjugates have been investigated in conjunction with tandem mass spectrometry of ESI-MS/MS. There were three characteristic fragment ions in the positive ion ESI mass spectra, which were the Na adduct ions with loss of steroidal moiety, amino acid ester moiety from pseudo molecular ion （M＋Na）^＋, and the phosphoamino acid methyl ester Na adduct ion by α-cleavage of the phosphora- midate respectively. The main fragment ions in negative ion ESI mass spectra were the ion （M-HN3）^-, the ion （M - AZT- H）^-, and the ion （M-steroidal moiety-H）^- besides the pseudo molecular ion （M-H）^-. The fragmentation patterns did not depend on the attached amino acid ester moiety.
基金The authors would like to thank the financial supports from the National Natural Science Foundation of China(No.29902003,20132020 and 20175026),the Ministry of Science and Technology,the Chinese Ministry of Education and Tsinghua University.
文摘Dinucleotide (TpAZT) phosphoramidates were synthesized by Todd reaction of dinucleoside H-phosphonates and amino acid methyl esters, and their diastereomers (Rp and Sp) were separated by crystallization, and the results showed that natural and cheap methyl esters of alanine and phenylalanine can be used for large-scale synthesis of dinucleotide analogs.
基金Project supported by the National Natural Science Foundation of China (Grant No. 29872023)the Ministry of Education of China (Research Funds for Chinese Scholars returning from abroad)China Postdoctoral Science Foundation
文摘Two chiral phosporamidates, (R)-(–)-1, 1′-binaphthyl-2, 2′dihydroxy-N- [α-(S)-methylbenzyl] phosphoramidate and (–)-1,1′-biphenyl-2,2′-dihydroxy-N-[α-(S)-methylbenzyl]-phosphoramidate were synthesized. Their crystal structures were determined by X-ray single crystal diffraction analysis. The phosphoramidate molecules are self-associated by intermolecular NH ···O = P hydrogen bonds and aromatic edge to face interactions.
文摘以三氯氧磷、1,3-丙二醇、N-羟乙基哌嗪为原料,合成了磷酰胺酯类化合物PN1,并利用PN1与氯磷酸二乙酯的亲核反应制备了磷酰胺酯类化合物PN2.采用核磁共振(nuclear magnetic resonance,NMR)1 H谱和13C谱、傅里叶变换红外光谱(Fourier transform infrared spectroscopy,FT-IR)、高分辨率质谱(high resolution mass spectroscopy,HRMS)表征了PN1和PN2的结构.采用二浸二轧的工艺,将不同质量分数(2%~27%)的PN1和PN2溶液应用于棉织物整理,研究其阻燃性能.经PN1整理后,棉织物的极限氧指数(LOI)从18%最高可提升至30.1%,在600℃时的成碳率从8%最高可上升至41.8%;经PN2整理后,棉织物的LOI从18%最高可提升至33.1%,在600℃时的成碳率从8%最高可上升至44.3%.
基金Ministry of Science and Technology of China(Grant No.2012ZX09103101-042)
文摘A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL biomarker for NSCLC） and human epidermal growth factor 2 （HER2, biomarker for breast cancer） with IC50 of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os （PO） administration of 6d in rat model （10 mg/kg） resulted in a moderate tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.
