We report an immobilized enzyme-catalyzed batch and continuous-flow synthesis of optically pure ethyl(R)-pantothenate((R)-PaOEt),the direct precursor of d-pantothenic acid.Firstly,a ketoreductase mutant designated as ...We report an immobilized enzyme-catalyzed batch and continuous-flow synthesis of optically pure ethyl(R)-pantothenate((R)-PaOEt),the direct precursor of d-pantothenic acid.Firstly,a ketoreductase mutant designated as M2,carrying two-point mutations of F97L and M242F relative to the wild-type SSCR,was constructed by site-directed mutagenesis,exhibited simultaneously improved activity toward ethyl 2′-ketopantothenate(K-PaOEt)and isopropanol,and could effectively catalyze the stereoselective reduction of K-PaOEt to(R)-PaOEt by using isopropanol as the sacrificial co-substrate to regenerate NADPH.After screening six commercially available carriers,an amino resin LXTE-700 was identified as the best solid support for the immobilization of M2 via the glutaraldehyde activation method.Upon optimization of the immobilization process and reaction conditions,the fabricated immobilized enzyme M2@amino resin demonstrated excellent recyclability and reusability,with the complete conversion of K-PaOEt to(R)-PaOEt being still realized after 12 cycles of reuse.Finally,M2@amino resin-catalyzed synthesis of(R)-PaOEt was successfully implemented in continuous-flow,accomplishing a 6.3 times higher space-time yield than that with the batch synthesis(529.2 versus 84 g L^(-1) d^(-1)).Our developed flow biocatalysis system also features an outstanding operational stability,as evidenced by the 100%conversion rate achieved after 15 consecutive days of operation.展开更多
Herein,the liquid-solid mass trans fer characteristics in micropacked bed reactors(μPBRs)operated with immiscible liquid-liquid two-phase flow is experimentally investigated.It is found that the overall volumetric li...Herein,the liquid-solid mass trans fer characteristics in micropacked bed reactors(μPBRs)operated with immiscible liquid-liquid two-phase flow is experimentally investigated.It is found that the overall volumetric liquid-solid mass transfer coefficient(k_(s)a)increases with the total flow rate and the channelto-particle diameter ratio,while decreases with the organic-to-aqueous phase flow rate ratio.A satisfactory correlation model for calculating k_(s)a of the liquid-liquid μPBRs is developed.The new knowledge obtained would be useful in guiding the design and optimization of the liquid-liquid μPBRs.展开更多
In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones ...In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55μmol/L to 0.018μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018μmol/L,CC_(50)=194μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR)and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.展开更多
A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compound...A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with EC50values in the range of 0.18–51.88 μmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity(EC50= 0.18 μmol/L, and 0.20 μmol/L) with higher selectivity(SI = 907, and 665) as comparison with the lead compound 6(EC50= 0.59 μmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and E138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HEPT.展开更多
We report here a generic,green synthesis of 17 valuable syn-aryl-(2S,3R)-2–chloro-3–hydroxy esters(syn-(2S,3R)-1)in 73%-99%isolated yields along with 6.1:1–83:1 dr and 31%~>99%ee,through dynamic reductive kineti...We report here a generic,green synthesis of 17 valuable syn-aryl-(2S,3R)-2–chloro-3–hydroxy esters(syn-(2S,3R)-1)in 73%-99%isolated yields along with 6.1:1–83:1 dr and 31%~>99%ee,through dynamic reductive kinetic resolution of racemic arylα–chloroβ-keto esters(2)catalyzed by an engineered ketoreductase which was obtained via ep PCR-based directed evolution.The hectogram scale synthesis of syn-(2S,3R)-1b at a substrate concentration of 120 g/L showcased the application potential of the biocatalytic method developed presently.展开更多
The utilization of readily available amino acids,which is not only an oxygen nucleophile but also a nitrogen nucleophile,in palladium-catalyzed allylic substitution is realized under mild conditions.The chemoselectivi...The utilization of readily available amino acids,which is not only an oxygen nucleophile but also a nitrogen nucleophile,in palladium-catalyzed allylic substitution is realized under mild conditions.The chemoselectivity and multiple allylation are controlled by adjusting the reaction conditions.This represents the first example of this convenient access to valuable N,O-diallylated amino acids.Under the title conditions,a range of amino acids(α-,β-,γ-)and dipeptides can be readily converted in to the corresponding allylic products with excellent yields(67 examples,up to 99%yield)as well as good functional group tolerance.展开更多
Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation.The best compound 6 e with a sulfonyl scaffol...Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation.The best compound 6 e with a sulfonyl scaffold displayed EC(50)values of 0.0356μmol/L against WT and 0.0228μmol/L against HIV K103 N mutant strain.More pronounced,it had a lower cytotoxicity(CC(50)=99.6μmol/L),higher selectivity index(SIWT=2799,SIK103 N=4375)and better calculated logarithm of the octanol-water partition coefficient(cLogP)than the lead compound 3.Molecular docking and dynamics provided the binding modes of these compounds with reve rse transcriptase,explaining their activity.Collectively,the new compounds could be candidates for anti-HIV drug discovery.展开更多
A copper-catalyzed three-component reaction involving cyclic carbonates,elemental sulfur,and H-phosphonates is presented.It proceeds with excellent yields and provides an attractive approach for the construction of va...A copper-catalyzed three-component reaction involving cyclic carbonates,elemental sulfur,and H-phosphonates is presented.It proceeds with excellent yields and provides an attractive approach for the construction of valuable trisubstituted allenyl phosphorothioates using a one-step strategy.Moreover,this method can be easily adapted to large-scale preparation.展开更多
As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasin...As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions[Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of He La cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types.Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.展开更多
The concise syntheses of eight 13-methylprotoberberine(13-MePB)and eight enantioenriched 13-methyltetrahydroprotoberberine(13-MeTHPB)alkaloids have been achieved in a tactically modular fashion.This synthetic work fea...The concise syntheses of eight 13-methylprotoberberine(13-MePB)and eight enantioenriched 13-methyltetrahydroprotoberberine(13-MeTHPB)alkaloids have been achieved in a tactically modular fashion.This synthetic work features a one-pot metal-free Pictet-Spengler/Friedel-Crafts hydroxyalkylation/dehydration/oxidation sequence and a following highly enantioselective Ir-catalyzed hydrogenation.Given such brevity and modularity,our developed synthetic route would be greatly beneficial to the efficient syntheses of existing natural products and new fully synthetic variants of 13-MePB and 13-MeTHPB family.展开更多
Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts,biologically active scaffolds and functional materials.Compared...Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts,biologically active scaffolds and functional materials.Compared to the C-C axially chiral molecules,the synthesis of axially chiral anilide compounds is a challenge owing to the lower rotation barriers.Herein,the construction of chiral allylic amine bearing axial chirality and central chirality via Pd-catalyzed atroposelective N-allylic alkylation reaction of cyclic vinyl carbonates and sulfonamides is reported.A diverse range of chiral sulfonamides bearing axial chirality and central chirality were synthesized in high yields and excellent enantioselectivities(up to 92%yield and 99%ee).In addition,the practical application of this protocol was also demonstrated by gram-scale synthesis and derivatives of the compound.展开更多
Aza-Heck cyclization of alkene-tethered oxime esters has received considerable attention as an effective strategy for synthesizing 1-pyrroline derivatives.However,the achievement of tandem aza-Heck reaction with alkyl...Aza-Heck cyclization of alkene-tethered oxime esters has received considerable attention as an effective strategy for synthesizing 1-pyrroline derivatives.However,the achievement of tandem aza-Heck reaction with alkyl electrophiles remains a challenge.Herein,we report a palladium-catalyzed tandem aza-Heck reaction of alkenetethered oxime esters with cyclopropanols.This catalytic system features mild conditions and broad substrate scopes,allowing the direct synthesis of structurally diverse 1-pyrroline derivatives in good yields.展开更多
Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last ...Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last 20 years,our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs,including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine(HEPT),thio-dihydro-alkoxy-benzyl-oxopyrimidine(S-DABO),diaryltriazine(DATA),diarylpyrimidine(DAPY)analogues,and their hybrid derivatives.Application of integrated modern medicinal strategies,including structure-based drug design,fragment-based optimization,scaffold/fragment hopping,molecular/fragment hybridization,and bioisosterism,led to the development of several highly potent analogues for further evaluations.In this paper,we review the development of NNRTIs in the last two decades using the above optimization strategies,including their structure-activity relationships,molecular modeling,and their binding modes with HIV-1 reverse transcriptase(RT).Future directions and perspectives on the design and associated challenges are also discussed.展开更多
In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines(NP-DATAs),synthesis of a series of novel biphenyl-substituted diaryltriazines(BP-DATAs)with a flexible side chain att...In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines(NP-DATAs),synthesis of a series of novel biphenyl-substituted diaryltriazines(BP-DATAs)with a flexible side chain attached at the C-6 position is presented.These compounds exhibited excellent potency against wild-type(WT)HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains.Compounds 5 j and 6 k had the best activity against WT,single and double HIV-1 mutants and reverse transcriptase(RT)enzyme comparable to two reference drugs(EFV and ETR)and our lead compound NP-DATA(1).Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket(NNIBP)attributing to the improved activity.The preliminary structure-activity relationship and PK profiles were also discussed.展开更多
Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(EC_(50)=1.0 nmol/L),but the poor metabolic stability in human liver microsomes(t_(1/2)=1...Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(EC_(50)=1.0 nmol/L),but the poor metabolic stability in human liver microsomes(t_(1/2)=14.6 min)and insufficient selectivity(SI=2059)with high cytotoxicity(CC_(50)=2.08μmol/L)remained major issues associated with JK-4b.The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b,leading to the discovery of a novel series of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain(EC_(50)=1.8–349 nmol/L).The best compound 5t in this collection(EC_(50)=1.8 nmol/L,CC_(50)=117μmol/L)was 32-fold in selectivity(SI=66,443)compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains,such as L100I,K103N,E138K,and Y181C.The metabolic stability of 5t was also significantly improved(t_(1/2)=74.52 min),approximately 5-fold higher than JK-4b in human liver microsomes(t_(1/2)=14.6 min).Also,5t possessed good stability in both human and monkey plasma.No significant in vitro inhibition effect toward CYP enzyme and hERG was observed.The single-dose acute toxicity test did not induce mice death or obvious pathological damage.These findings pave the way for further development of 5t as a drug candidate.展开更多
Since accelerated metabolism produces much higher levels of reactive oxygen species(ROS)in cancer cells compared to ROS levels found in normal cells,human MutT homolog 1(MTH1),which sanitizes oxidized nucleotide pools...Since accelerated metabolism produces much higher levels of reactive oxygen species(ROS)in cancer cells compared to ROS levels found in normal cells,human MutT homolog 1(MTH1),which sanitizes oxidized nucleotide pools,was recently demonstrated to be crucial for the survival of cancer cells,but not required for the proliferation of normal cells.Therefore,dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells.While several inhibitors were indeed confirmed to be effective,some inhibitors failed to kill cancer cells,complicating MTH1 as a viable target for cancer eradication.In this review,we summarize the current status of developing MTH1 inhibitors as drug candidates,classify the MTH1 inhibitors based on their structures,and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.展开更多
The total synthesis of natural products is constantly facing many challenges derived from the complexed chemical structures,the lengthy synthetic routes,the time-consuming workup procedures and the large environmental...The total synthesis of natural products is constantly facing many challenges derived from the complexed chemical structures,the lengthy synthetic routes,the time-consuming workup procedures and the large environmental footprint.In the past two decades,performing chemical transformations in continuous flow using various types of microreactors and in-line auxiliary technologies have been demonstrated effectively in respects of enhanced re-action yield and selectivity,excellent reproducibility and easy scale-up,safe proceeding hazardous reaction.And the rapid synthesis of natural products,which has been enabled in continuous flow based upon the significant improvement of overall yield within a short residence time via processing intensification and systematic auto-mation,is essential to furnish sufficient quantity for the bioactivity investigation of structural diversity modifi-cation,structure-activity relationship during drug discovery and the increasing consumption of medical treatment.In this review,the multi-step continuous flow synthesis of natural products is highlighted to provide a comprehensive recognization on the intrinsic merits of flow chemistry for organic chemists to purposefully develop the flow synthetic approaches of natural products in the future.展开更多
Comprehensive Summary HpnG plays a crucial role in the production of ribosylhopane,a key intermediate in the biosynthesis of bacteriohopanepolyol.Despite early extensive studies,the precise function of HpnG has remain...Comprehensive Summary HpnG plays a crucial role in the production of ribosylhopane,a key intermediate in the biosynthesis of bacteriohopanepolyol.Despite early extensive studies,the precise function of HpnG has remained elusive.Here,we report functional characterization of HpnG as a purine nucleoside phosphorylase,which converts adenosylhopane to phosphoribosylhopane in the presence of phosphate.HpnG demonstrates broad substrate specificity and impressive stability,making it a valuable enzymatic tool for applications in nucleoside processing and related biotechnology.展开更多
Visible light-mediated site-specific C(sp^(3))-H xanthylation of amides has been accomplished using N-xanthylamides.The N-centered radicals generated by light initiation of N-xanthylamide substrates undergo 1,5-hydrog...Visible light-mediated site-specific C(sp^(3))-H xanthylation of amides has been accomplished using N-xanthylamides.The N-centered radicals generated by light initiation of N-xanthylamide substrates undergo 1,5-hydrogen atom transfer to form benzylic or alkyl radical intermediates under metal-and catalyst-free conditions.This method exhibits a broad substrate scope,high functional group tolerance,and high regioselectivity.Furthermore,this strategy provides straightforward access to a range of derivatives through the subsequent elaboration of the xanthate group.展开更多
The enantioselective total synthesis of representative members of the eburnamine-vincamine alkaloids(+)-vincamine,(-)-eburnamonine,and(-)-criocerine has been accomplished.The synthesis took advantage of a highly stere...The enantioselective total synthesis of representative members of the eburnamine-vincamine alkaloids(+)-vincamine,(-)-eburnamonine,and(-)-criocerine has been accomplished.The synthesis took advantage of a highly stereoselective Ir-catalyzed hydrogenation/lactamization cascade reaction,which allows for the stereo-selective construction of the C/D rings as well as the installation of the critical cis-C20/C21 relative stereo-chemistry of the eburnamine-vincamine alkaloid skeleton in one pot.展开更多
基金the Science and Technology R&D Major Project of Jiangxi Province(No.20244AFI92001)the National Natural Science Foundation of China(Nos.22071033 and 21801047)for the financial supports.
文摘We report an immobilized enzyme-catalyzed batch and continuous-flow synthesis of optically pure ethyl(R)-pantothenate((R)-PaOEt),the direct precursor of d-pantothenic acid.Firstly,a ketoreductase mutant designated as M2,carrying two-point mutations of F97L and M242F relative to the wild-type SSCR,was constructed by site-directed mutagenesis,exhibited simultaneously improved activity toward ethyl 2′-ketopantothenate(K-PaOEt)and isopropanol,and could effectively catalyze the stereoselective reduction of K-PaOEt to(R)-PaOEt by using isopropanol as the sacrificial co-substrate to regenerate NADPH.After screening six commercially available carriers,an amino resin LXTE-700 was identified as the best solid support for the immobilization of M2 via the glutaraldehyde activation method.Upon optimization of the immobilization process and reaction conditions,the fabricated immobilized enzyme M2@amino resin demonstrated excellent recyclability and reusability,with the complete conversion of K-PaOEt to(R)-PaOEt being still realized after 12 cycles of reuse.Finally,M2@amino resin-catalyzed synthesis of(R)-PaOEt was successfully implemented in continuous-flow,accomplishing a 6.3 times higher space-time yield than that with the batch synthesis(529.2 versus 84 g L^(-1) d^(-1)).Our developed flow biocatalysis system also features an outstanding operational stability,as evidenced by the 100%conversion rate achieved after 15 consecutive days of operation.
文摘Herein,the liquid-solid mass trans fer characteristics in micropacked bed reactors(μPBRs)operated with immiscible liquid-liquid two-phase flow is experimentally investigated.It is found that the overall volumetric liquid-solid mass transfer coefficient(k_(s)a)increases with the total flow rate and the channelto-particle diameter ratio,while decreases with the organic-to-aqueous phase flow rate ratio.A satisfactory correlation model for calculating k_(s)a of the liquid-liquid μPBRs is developed.The new knowledge obtained would be useful in guiding the design and optimization of the liquid-liquid μPBRs.
基金financial support from the National Natural Science Foundation of China(Nos.21967020,U1702286,21362017,21262044)Program for Changjiang Scholars and Innovative Research Team in University(No.IRT17R94,China)Fund of Academician Working Station of Yunnan Province(No.2018IC057)。
文摘In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55μmol/L to 0.018μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018μmol/L,CC_(50)=194μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR)and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.
基金financially supported by National Natural Science Foundation of China (No. 22077018)National Key R&D Program of China (No. 2017YFA0506000)。
文摘A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with EC50values in the range of 0.18–51.88 μmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity(EC50= 0.18 μmol/L, and 0.20 μmol/L) with higher selectivity(SI = 907, and 665) as comparison with the lead compound 6(EC50= 0.59 μmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and E138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HEPT.
基金The National Key Research and Development Program of China(Nos.2021YFA0911400 and 2021YFF0600704)the National Natural Science Foundation of China(Nos.22071033 and 21801047)are acknowledged for the financial supports。
文摘We report here a generic,green synthesis of 17 valuable syn-aryl-(2S,3R)-2–chloro-3–hydroxy esters(syn-(2S,3R)-1)in 73%-99%isolated yields along with 6.1:1–83:1 dr and 31%~>99%ee,through dynamic reductive kinetic resolution of racemic arylα–chloroβ-keto esters(2)catalyzed by an engineered ketoreductase which was obtained via ep PCR-based directed evolution.The hectogram scale synthesis of syn-(2S,3R)-1b at a substrate concentration of 120 g/L showcased the application potential of the biocatalytic method developed presently.
基金financial support from the National Natural Science Foundation of China(No.21602144)the Science and Technology Program of Sichuan Province(No.2018JY0485)Scientific Research Project of Education Department of Hubei Province(Nos.Q20211503,B2020057)。
文摘The utilization of readily available amino acids,which is not only an oxygen nucleophile but also a nitrogen nucleophile,in palladium-catalyzed allylic substitution is realized under mild conditions.The chemoselectivity and multiple allylation are controlled by adjusting the reaction conditions.This represents the first example of this convenient access to valuable N,O-diallylated amino acids.Under the title conditions,a range of amino acids(α-,β-,γ-)and dipeptides can be readily converted in to the corresponding allylic products with excellent yields(67 examples,up to 99%yield)as well as good functional group tolerance.
基金financially supported by the National Natural Science Foundation of China(No.21372050)National Key R&D Program of China(No.2017YFA0506000)the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology(No.2017QNRC061)。
文摘Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation.The best compound 6 e with a sulfonyl scaffold displayed EC(50)values of 0.0356μmol/L against WT and 0.0228μmol/L against HIV K103 N mutant strain.More pronounced,it had a lower cytotoxicity(CC(50)=99.6μmol/L),higher selectivity index(SIWT=2799,SIK103 N=4375)and better calculated logarithm of the octanol-water partition coefficient(cLogP)than the lead compound 3.Molecular docking and dynamics provided the binding modes of these compounds with reve rse transcriptase,explaining their activity.Collectively,the new compounds could be candidates for anti-HIV drug discovery.
基金supported by the Educational Foundation of Zhejiang University of Technology(No.KYY-HX-20220471)。
文摘A copper-catalyzed three-component reaction involving cyclic carbonates,elemental sulfur,and H-phosphonates is presented.It proceeds with excellent yields and provides an attractive approach for the construction of valuable trisubstituted allenyl phosphorothioates using a one-step strategy.Moreover,this method can be easily adapted to large-scale preparation.
文摘As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions[Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of He La cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types.Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.
基金supported by the National Natural Science Foundation of China(No.U21A20278)Sichuan Science and Technology Program(No.2021YJ0221).
文摘The concise syntheses of eight 13-methylprotoberberine(13-MePB)and eight enantioenriched 13-methyltetrahydroprotoberberine(13-MeTHPB)alkaloids have been achieved in a tactically modular fashion.This synthetic work features a one-pot metal-free Pictet-Spengler/Friedel-Crafts hydroxyalkylation/dehydration/oxidation sequence and a following highly enantioselective Ir-catalyzed hydrogenation.Given such brevity and modularity,our developed synthetic route would be greatly beneficial to the efficient syntheses of existing natural products and new fully synthetic variants of 13-MePB and 13-MeTHPB family.
基金supported by the Educational Foundation of Zhejiang University of Technology(No.KYY-HX-20220471).
文摘Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts,biologically active scaffolds and functional materials.Compared to the C-C axially chiral molecules,the synthesis of axially chiral anilide compounds is a challenge owing to the lower rotation barriers.Herein,the construction of chiral allylic amine bearing axial chirality and central chirality via Pd-catalyzed atroposelective N-allylic alkylation reaction of cyclic vinyl carbonates and sulfonamides is reported.A diverse range of chiral sulfonamides bearing axial chirality and central chirality were synthesized in high yields and excellent enantioselectivities(up to 92%yield and 99%ee).In addition,the practical application of this protocol was also demonstrated by gram-scale synthesis and derivatives of the compound.
基金the funding support of the National Key R&D Program of China(No.2021YFF0701601)NSFC(No.22271053,22031004and 21921003)+1 种基金STCSM(No.21ZR1445900)Shanghai Municipal Education Commission(No.20212308).
文摘Aza-Heck cyclization of alkene-tethered oxime esters has received considerable attention as an effective strategy for synthesizing 1-pyrroline derivatives.However,the achievement of tandem aza-Heck reaction with alkyl electrophiles remains a challenge.Herein,we report a palladium-catalyzed tandem aza-Heck reaction of alkenetethered oxime esters with cyclopropanols.This catalytic system features mild conditions and broad substrate scopes,allowing the direct synthesis of structurally diverse 1-pyrroline derivatives in good yields.
基金funded by grants from the National Natural Science Foundation of China(81872791 and 21372050)the Young Elite Scientists Sponsorship Program by the China Association forScience and Technology(2017QNRC061)+1 种基金National Key R&D Program of China(2017YFA0506000)the Key Research and Development Program of Ningxia(2019BFG02017 and 2018BFH02001,China)
文摘Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV treatment.In the last 20 years,our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs,including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine(HEPT),thio-dihydro-alkoxy-benzyl-oxopyrimidine(S-DABO),diaryltriazine(DATA),diarylpyrimidine(DAPY)analogues,and their hybrid derivatives.Application of integrated modern medicinal strategies,including structure-based drug design,fragment-based optimization,scaffold/fragment hopping,molecular/fragment hybridization,and bioisosterism,led to the development of several highly potent analogues for further evaluations.In this paper,we review the development of NNRTIs in the last two decades using the above optimization strategies,including their structure-activity relationships,molecular modeling,and their binding modes with HIV-1 reverse transcriptase(RT).Future directions and perspectives on the design and associated challenges are also discussed.
基金financially supported by National Natural Science Foundation of China under Grant Nos.21871055 and21372050Shanghai Municipal Natural Science Foundation under Grant No.13ZR1402200(China).
文摘In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines(NP-DATAs),synthesis of a series of novel biphenyl-substituted diaryltriazines(BP-DATAs)with a flexible side chain attached at the C-6 position is presented.These compounds exhibited excellent potency against wild-type(WT)HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains.Compounds 5 j and 6 k had the best activity against WT,single and double HIV-1 mutants and reverse transcriptase(RT)enzyme comparable to two reference drugs(EFV and ETR)and our lead compound NP-DATA(1).Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket(NNIBP)attributing to the improved activity.The preliminary structure-activity relationship and PK profiles were also discussed.
基金supported by National Natural Science Foundation of China(Nos.21871055 and 22077018)'National Key R&D Program of China(2017YFA0506000).
文摘Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(EC_(50)=1.0 nmol/L),but the poor metabolic stability in human liver microsomes(t_(1/2)=14.6 min)and insufficient selectivity(SI=2059)with high cytotoxicity(CC_(50)=2.08μmol/L)remained major issues associated with JK-4b.The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b,leading to the discovery of a novel series of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain(EC_(50)=1.8–349 nmol/L).The best compound 5t in this collection(EC_(50)=1.8 nmol/L,CC_(50)=117μmol/L)was 32-fold in selectivity(SI=66,443)compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains,such as L100I,K103N,E138K,and Y181C.The metabolic stability of 5t was also significantly improved(t_(1/2)=74.52 min),approximately 5-fold higher than JK-4b in human liver microsomes(t_(1/2)=14.6 min).Also,5t possessed good stability in both human and monkey plasma.No significant in vitro inhibition effect toward CYP enzyme and hERG was observed.The single-dose acute toxicity test did not induce mice death or obvious pathological damage.These findings pave the way for further development of 5t as a drug candidate.
基金funded by the grant from the National Natural Science Foundation of China(81903425,to Yizhen Yin)
文摘Since accelerated metabolism produces much higher levels of reactive oxygen species(ROS)in cancer cells compared to ROS levels found in normal cells,human MutT homolog 1(MTH1),which sanitizes oxidized nucleotide pools,was recently demonstrated to be crucial for the survival of cancer cells,but not required for the proliferation of normal cells.Therefore,dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells.While several inhibitors were indeed confirmed to be effective,some inhibitors failed to kill cancer cells,complicating MTH1 as a viable target for cancer eradication.In this review,we summarize the current status of developing MTH1 inhibitors as drug candidates,classify the MTH1 inhibitors based on their structures,and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.
基金support from the National Key Research and Development Program of China(Nos.2021YFC2101900,2021YFF0600704)the National Natural Science Foundation of China(Nos.21908029,22178066)Start-up Fund of Fudan University(No.JIH1615026Y)is gratefully acknowledged.
文摘The total synthesis of natural products is constantly facing many challenges derived from the complexed chemical structures,the lengthy synthetic routes,the time-consuming workup procedures and the large environmental footprint.In the past two decades,performing chemical transformations in continuous flow using various types of microreactors and in-line auxiliary technologies have been demonstrated effectively in respects of enhanced re-action yield and selectivity,excellent reproducibility and easy scale-up,safe proceeding hazardous reaction.And the rapid synthesis of natural products,which has been enabled in continuous flow based upon the significant improvement of overall yield within a short residence time via processing intensification and systematic auto-mation,is essential to furnish sufficient quantity for the bioactivity investigation of structural diversity modifi-cation,structure-activity relationship during drug discovery and the increasing consumption of medical treatment.In this review,the multi-step continuous flow synthesis of natural products is highlighted to provide a comprehensive recognization on the intrinsic merits of flow chemistry for organic chemists to purposefully develop the flow synthetic approaches of natural products in the future.
基金supported by grants from the National Key Research andDevelopmenttProgram(2018YFA0900402,2021YFA0910501)the National Natural Science Foundation of China(21921003,32270070,32270050,U22A20451)+1 种基金the Funding of Innovative Research Team of High-Level Local Universities in Shanghai and a key laboratory program of the Education Commission of Shanghai Municipality(ZDSYS14005)West Light Foundation of The Chinese Academy of Sciences(xbzg-zdsys-202105).
文摘Comprehensive Summary HpnG plays a crucial role in the production of ribosylhopane,a key intermediate in the biosynthesis of bacteriohopanepolyol.Despite early extensive studies,the precise function of HpnG has remained elusive.Here,we report functional characterization of HpnG as a purine nucleoside phosphorylase,which converts adenosylhopane to phosphoribosylhopane in the presence of phosphate.HpnG demonstrates broad substrate specificity and impressive stability,making it a valuable enzymatic tool for applications in nucleoside processing and related biotechnology.
基金We acknowledge financial support from the National Natural Science Foundation of China(No.21602144)the Scientific Research Project of the Education Department of Hubei Province(No.Q20211503)the Science and Technology Program of Sichuan Province(No.2021ZYD0064).
文摘Visible light-mediated site-specific C(sp^(3))-H xanthylation of amides has been accomplished using N-xanthylamides.The N-centered radicals generated by light initiation of N-xanthylamide substrates undergo 1,5-hydrogen atom transfer to form benzylic or alkyl radical intermediates under metal-and catalyst-free conditions.This method exhibits a broad substrate scope,high functional group tolerance,and high regioselectivity.Furthermore,this strategy provides straightforward access to a range of derivatives through the subsequent elaboration of the xanthate group.
基金support from the National Natural Science Foundation of China(No.U21A20278)the Sichuan Science and Technology Program(No.2021YJ0221).
文摘The enantioselective total synthesis of representative members of the eburnamine-vincamine alkaloids(+)-vincamine,(-)-eburnamonine,and(-)-criocerine has been accomplished.The synthesis took advantage of a highly stereoselective Ir-catalyzed hydrogenation/lactamization cascade reaction,which allows for the stereo-selective construction of the C/D rings as well as the installation of the critical cis-C20/C21 relative stereo-chemistry of the eburnamine-vincamine alkaloid skeleton in one pot.
