Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-fre...Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-free total synthesis of cabucine oxindole A,a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine.Key transformations of our approach include a one-step,organocatalytic and enantioselective construction of the spiro[pyrrolidine-3,3'-oxindole]moiety and a Korte rearrangement to furnish the final dihydropyran motif.Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT-4 and MCF7 cell line inhibitor.展开更多
As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dys...As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.展开更多
Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endoge...Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endogenous cannabinoid(EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosisseverity, while its levels in normal liver tissue are high;in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that[18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.展开更多
基金Financial support from SZSTI(Nos.JCY120170817110515599,KQTD20150717103157174)the National Natural Science Founda tion of China(Nos.21772082 and 21971104)+3 种基金the Guangdong Innovative Program(No.2019BT02Y335)the Guangdong Provin cial Key Laboratory of Catalysis(No.2020B121201002)the Shen zhen Key Laboratory of Small Molecule Drug Discovery and Syn thesis(No.ZDSY520190902093215877)the Shenzhen Nobel Prize Scientists Laboratory Project(C17783101)is greatly appreci-ated.The authors are grateful to Prof.Qing Ye(SUSTech)for assis-tance with XRD analysis.
文摘Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-free total synthesis of cabucine oxindole A,a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine.Key transformations of our approach include a one-step,organocatalytic and enantioselective construction of the spiro[pyrrolidine-3,3'-oxindole]moiety and a Korte rearrangement to furnish the final dihydropyran motif.Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT-4 and MCF7 cell line inhibitor.
基金the financial support from the NIH grants (DA038000 and DA043507 to S. H. L. and DA033760 to B. F. C.)the Swiss National Science Foundation for a postdoctoral fellowship to Michael A. Schafroth (Grant No. P2EZP3_175137, Switzerland)。
文摘As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.
基金supported by MGH Research Scholars Program(to Raymond.T.Chung,USA)。
文摘Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endogenous cannabinoid(EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosisseverity, while its levels in normal liver tissue are high;in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that[18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.