This paper reports the results on the nature of bond-order and net charge distributions predicted by Ab initio Hartree- Fock procedures for 1-amino-2-iminio-, 1-amino-3-iminio- and 1-amino-4-iminiotropylium cations th...This paper reports the results on the nature of bond-order and net charge distributions predicted by Ab initio Hartree- Fock procedures for 1-amino-2-iminio-, 1-amino-3-iminio- and 1-amino-4-iminiotropylium cations that incorporate, in order, the 1,7-, 1,3- and 1,5-diazapentadienium (vinamidinium) elements. There appears to be very little contribution from tropylium-type charge distribution, the positive charges residing largely in the nitrogen atoms. The partial bond fixations and charge distributions show interesting variation in the three isomers. The 1,3-isomer in which the 1,3-diazapentadienium element is preserved in the favoured zigzag conformation appears to be relatively the best stabilized. The six isomeric benzo-fused derivatives arising from the three amino-iminiotropylium cations show similar differences in patterns of behaviour. Interestingly, the isomer in which a zigzag 1,3-diazapentadienium element is conjugated with a styrene moiety receives the deepest stabilization. While showing that the element largely contributes to the relative stabilization among the systems studied, contribution from certain stereochemical destabilizing factors may not be insignificant.展开更多
Chiral benzo-fused N-heterocycles are frequently found in natural and synthetic products.However,their synthesis usually suffers from different limitations such as difficulty in accessing appropriate starting material...Chiral benzo-fused N-heterocycles are frequently found in natural and synthetic products.However,their synthesis usually suffers from different limitations such as difficulty in accessing appropriate starting materials and unsatisfactory stereoselectivities.In this work,an unprecedented chiral sulfide-catalyzed enantioselective Friedel-Crafts-type electrophilic chlorination is shown to construct various 3,4-functionalized tetrahydroquinolines with excellent enantio-and diastereoselectivities from readily available aniline derivatives.Interestingly,employing N-allyl 1-naphthanilides as substrates,divergent reactions via chlorocarbocyclization and dearomatization occurred to afford two chiral polycyclic benzo-fused N-heterocycles.The system that we developed extends the scope of asymmetric chlorination to general substrateswithout the need of a N-H group,and significantly promotes the synthesis of enantioenriched benzo-fused N-heterocycles.展开更多
Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from o...Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 mu mol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
文摘This paper reports the results on the nature of bond-order and net charge distributions predicted by Ab initio Hartree- Fock procedures for 1-amino-2-iminio-, 1-amino-3-iminio- and 1-amino-4-iminiotropylium cations that incorporate, in order, the 1,7-, 1,3- and 1,5-diazapentadienium (vinamidinium) elements. There appears to be very little contribution from tropylium-type charge distribution, the positive charges residing largely in the nitrogen atoms. The partial bond fixations and charge distributions show interesting variation in the three isomers. The 1,3-isomer in which the 1,3-diazapentadienium element is preserved in the favoured zigzag conformation appears to be relatively the best stabilized. The six isomeric benzo-fused derivatives arising from the three amino-iminiotropylium cations show similar differences in patterns of behaviour. Interestingly, the isomer in which a zigzag 1,3-diazapentadienium element is conjugated with a styrene moiety receives the deepest stabilization. While showing that the element largely contributes to the relative stabilization among the systems studied, contribution from certain stereochemical destabilizing factors may not be insignificant.
基金the National Natural Science Foundation of China(grant nos.91856109 and 21772239)the Fundamental Research Funds for the Central Universities(grant no.20lgzd21)the Leading Scientific,Technical and Innovation Talents of Guangdong Special Support Program(grant no.2019TX05Y638)for financial support.
文摘Chiral benzo-fused N-heterocycles are frequently found in natural and synthetic products.However,their synthesis usually suffers from different limitations such as difficulty in accessing appropriate starting materials and unsatisfactory stereoselectivities.In this work,an unprecedented chiral sulfide-catalyzed enantioselective Friedel-Crafts-type electrophilic chlorination is shown to construct various 3,4-functionalized tetrahydroquinolines with excellent enantio-and diastereoselectivities from readily available aniline derivatives.Interestingly,employing N-allyl 1-naphthanilides as substrates,divergent reactions via chlorocarbocyclization and dearomatization occurred to afford two chiral polycyclic benzo-fused N-heterocycles.The system that we developed extends the scope of asymmetric chlorination to general substrateswithout the need of a N-H group,and significantly promotes the synthesis of enantioenriched benzo-fused N-heterocycles.
基金financial support from the National Natural Science Foundation of China(Grants Nos.91229204 and 81220108025)Major Project of Chinese National Programs for Fundamental Research and Development(No.2015CB910304)+2 种基金National High Technology Research and Development Program of China(No.2012AA020302)National Basic Research Program of China(No.2012CB518005)National S&T Major Projects(Nos.2012ZX09103101-072,2014ZX09507002-001,and 2013ZX09507-001)
文摘Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 mu mol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
