On-resin peptide modification renders an easy-to-operate method that combines solid-phase peptide synthesis efficiency and avoids tedious purification procedures. Herein, we report the transition-metal-free and redox-...On-resin peptide modification renders an easy-to-operate method that combines solid-phase peptide synthesis efficiency and avoids tedious purification procedures. Herein, we report the transition-metal-free and redox-neutral approach for solid-phase Met diversification with substrate diversity, which could be applied to synthesize cyclic peptides of different sizes.展开更多
Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poo...Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poor bioavailability,the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy.Recently,a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified.In particular,few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors.This review summarizes the development and structureeactivity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies,with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity,higher oral bioavailability and better physicochemical properties.展开更多
Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gaq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma(UM) cases...Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gaq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma(UM) cases, making directly targeting Gaq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gaq/11 inhibitors, and identified GQ262 with improved Gaq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase(ERK), and yes-associated protein(YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gaq/11directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gaq/11 may be an efficient strategy against uveal melanoma.展开更多
Background To determine whether ex utero intrapartum treatment (EXIT) is an appropriate approach for managing fetuses antenatally diagnosed with giant congenital omphaloceles. Methods We retrospectively reviewed patie...Background To determine whether ex utero intrapartum treatment (EXIT) is an appropriate approach for managing fetuses antenatally diagnosed with giant congenital omphaloceles. Methods We retrospectively reviewed patients with omphaloceles who underwent either an EXIT procedure or a traditional repair surgery. Basic and clinical parameters including gender, gestational age, birth weight, maternal blood loss, operative times and operative complications were analyzed. During the 6–12-month follow-ups, postoperative complications including bowel obstruction, abdominal infections, postoperative abdominal distension were monitored, and survival rate was analyzed. Results A total of seven patients underwent the EXIT procedure and 11 patients underwent the traditional postnatal surgery. We found no differences in maternal age, gestational age at diagnosis, gestational age at delivery and birth weight between the two groups. In the EXIT group, the average operation time for mother was 68.3 ± 17.5 minutes and the average maternal blood loss was 233.0 ± 57.7 mL. The operation time in the EXIT group (22.0 ± 4.5 minutes) was shorter than that in the traditional group (35 ± 8.7 minutes), but the length of hospital stay in the EXIT group (20.5 ± 3.1 days) was longer than that in the traditional group (15.7 ± 2.5 days,P < 0.05). During the follow-up, one patient in the EXIT group had an intestinal obstruction, one developed abdominal compartment syndrome and one died in the traditional group. Conclusions In our experience, EXIT is a safe and effective procedure for the treatment of giant congenital omphaloceles. However, more experience is needed before this procedure can be widely recommended.展开更多
Site-selective modification of peptide/protein is a vital approach to disclose post-translational modifications(PTMs) and plays a crucial role in chemical biology, as well as drug development. Compared with synthetic ...Site-selective modification of peptide/protein is a vital approach to disclose post-translational modifications(PTMs) and plays a crucial role in chemical biology, as well as drug development. Compared with synthetic and chemical biology methods, chemical modification of native peptide/protein provides a more versatile approach to achieve late-stage diversification for functional studies. Lysine featured high nucleophilicity, frequency, and solvent accessibility, making its site-selective modification important but elusive. Herein, we reported a visible-light-driven and Cys-directed Lys site-selective stapling approach for peptide/protein. By cleavable Cys anchoring, site-selective Lys single-site modification was achieved, and this method could be applied to multi-functionalization.展开更多
An efficient asymmetric and enantio-swithchable organocatalytic[3+3]annulation reaction using MBH-2-naphthoates of nitroalkenes and 4-hydroxyquinolin-2(1H)-ones has been developed.Densely substituted tetrahydropyrano[...An efficient asymmetric and enantio-swithchable organocatalytic[3+3]annulation reaction using MBH-2-naphthoates of nitroalkenes and 4-hydroxyquinolin-2(1H)-ones has been developed.Densely substituted tetrahydropyrano[3,2-c]qui noli nones scaffolds with two adjacent stereogenic centers are obtained with high yield(up to 95%yield)and good stereoselectivities(up to>20:1 dr and 96%ee)in an enantio-switchable manner.Furthermore,gram scale synthesis was achieved and the nitro group could easily transform into an amino group without any appreciable loss in the diastereo-and enantioselectivity.展开更多
基金financial supported by the National Natural Science Foundation of China (No. 22077144)Guangdong Natural Science Funds for Distinguished Young Scholar (No.2018B030306017)+1 种基金Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (No. 2019B030301005)Key Research and Development Program of Guangdong Province (No.2020B1111110003)。
文摘On-resin peptide modification renders an easy-to-operate method that combines solid-phase peptide synthesis efficiency and avoids tedious purification procedures. Herein, we report the transition-metal-free and redox-neutral approach for solid-phase Met diversification with substrate diversity, which could be applied to synthesize cyclic peptides of different sizes.
基金financial support by Guangdong Natural Science Funds for Distinguished Young Scholar(No.2018B030306017,China)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(2018)+4 种基金National Natural Science Foundation of China(Nos.81602972,81673436 and 91853109,China)The Fundamental Research Funds for the Central Universities(20ykzd15,China)Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery(2019B030301005,China)Guangzhou Science and Technology Project(202002020082,China)Key-Area Research and Development Program of Guangdong Province(2020B1111110003,China)
文摘Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poor bioavailability,the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy.Recently,a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified.In particular,few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors.This review summarizes the development and structureeactivity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies,with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity,higher oral bioavailability and better physicochemical properties.
基金financial support by National Natural Science Foundation of China (No.22077144 and 81973359)Guangdong Natural Science Funds for Distinguished Young Scholar (No.2018B030306017,China)+4 种基金Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2019B030301005,China)Key Reasearch and Development Program of Guangdong Province (2020B1111110003,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093,China)National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province,2017B090903004)Jilin Province Science and Technology Development Project (20200404105YY)。
文摘Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gaq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma(UM) cases, making directly targeting Gaq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gaq/11 inhibitors, and identified GQ262 with improved Gaq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase(ERK), and yes-associated protein(YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gaq/11directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gaq/11 may be an efficient strategy against uveal melanoma.
基金supported by Grants from the National Natural Science Foundation of China(Nos.81270441,81401240)
文摘Background To determine whether ex utero intrapartum treatment (EXIT) is an appropriate approach for managing fetuses antenatally diagnosed with giant congenital omphaloceles. Methods We retrospectively reviewed patients with omphaloceles who underwent either an EXIT procedure or a traditional repair surgery. Basic and clinical parameters including gender, gestational age, birth weight, maternal blood loss, operative times and operative complications were analyzed. During the 6–12-month follow-ups, postoperative complications including bowel obstruction, abdominal infections, postoperative abdominal distension were monitored, and survival rate was analyzed. Results A total of seven patients underwent the EXIT procedure and 11 patients underwent the traditional postnatal surgery. We found no differences in maternal age, gestational age at diagnosis, gestational age at delivery and birth weight between the two groups. In the EXIT group, the average operation time for mother was 68.3 ± 17.5 minutes and the average maternal blood loss was 233.0 ± 57.7 mL. The operation time in the EXIT group (22.0 ± 4.5 minutes) was shorter than that in the traditional group (35 ± 8.7 minutes), but the length of hospital stay in the EXIT group (20.5 ± 3.1 days) was longer than that in the traditional group (15.7 ± 2.5 days,P < 0.05). During the follow-up, one patient in the EXIT group had an intestinal obstruction, one developed abdominal compartment syndrome and one died in the traditional group. Conclusions In our experience, EXIT is a safe and effective procedure for the treatment of giant congenital omphaloceles. However, more experience is needed before this procedure can be widely recommended.
基金supported by Guangdong Natural Science Funds for Distinguished Young Scholar (2018B030306017)the National Natural Science Foundation of China (22077144)+1 种基金Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2019B030301005)Key Research and Development Program of Guangdong Province (2020B1111110003)。
文摘Site-selective modification of peptide/protein is a vital approach to disclose post-translational modifications(PTMs) and plays a crucial role in chemical biology, as well as drug development. Compared with synthetic and chemical biology methods, chemical modification of native peptide/protein provides a more versatile approach to achieve late-stage diversification for functional studies. Lysine featured high nucleophilicity, frequency, and solvent accessibility, making its site-selective modification important but elusive. Herein, we reported a visible-light-driven and Cys-directed Lys site-selective stapling approach for peptide/protein. By cleavable Cys anchoring, site-selective Lys single-site modification was achieved, and this method could be applied to multi-functionalization.
基金financial support from the National Natural Science Foundation of China(No.81602972)Guangdong Natural Science Funds for Distinguished Young Scholar(No.2018B030306017)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(2018)。
文摘An efficient asymmetric and enantio-swithchable organocatalytic[3+3]annulation reaction using MBH-2-naphthoates of nitroalkenes and 4-hydroxyquinolin-2(1H)-ones has been developed.Densely substituted tetrahydropyrano[3,2-c]qui noli nones scaffolds with two adjacent stereogenic centers are obtained with high yield(up to 95%yield)and good stereoselectivities(up to>20:1 dr and 96%ee)in an enantio-switchable manner.Furthermore,gram scale synthesis was achieved and the nitro group could easily transform into an amino group without any appreciable loss in the diastereo-and enantioselectivity.