A series of heterocycle-substituted phthalimide derivatives were synthesized.Structurally diverse derivatives with heterocyclic rings,including furan,imidazo[1,2-a]pyridine,1,3,4-thiadiazine,imidazo[2,1-b][1,3,4]thiad...A series of heterocycle-substituted phthalimide derivatives were synthesized.Structurally diverse derivatives with heterocyclic rings,including furan,imidazo[1,2-a]pyridine,1,3,4-thiadiazine,imidazo[2,1-b][1,3,4]thiadiazine,pyrazole,1,2,4-triazolo[3,4- b][1,3,4]thiadiazine,thiazole and thiazoline,were obtained by the reactions ofα-bromoketone intermediate with various nucleophiles containing oxygen,nitrogen and sulfur atom.Their cytotoxic activity was also evaluated against five human cancer cell lines in vitro.展开更多
FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats.In this study,FTY720 or IMMH002 analogues(...FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats.In this study,FTY720 or IMMH002 analogues(21-24)were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms.Target compounds were synthesized via a convergent route using the key and optically pure building block 9,which was first synthesized via asymmetrically catalyzed amination.The phosphorylation rates of these analogues in rat or human blood were compared.The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound,whereas compound 23 showed improvements in rats,but not in humans.In pharmacokinetics studies of rats,compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002.Thus,our study not only yielded new compounds with therapeutic potential,but also showed species differences between rats and humans in response to the structural modifications,which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.展开更多
文摘A series of heterocycle-substituted phthalimide derivatives were synthesized.Structurally diverse derivatives with heterocyclic rings,including furan,imidazo[1,2-a]pyridine,1,3,4-thiadiazine,imidazo[2,1-b][1,3,4]thiadiazine,pyrazole,1,2,4-triazolo[3,4- b][1,3,4]thiadiazine,thiazole and thiazoline,were obtained by the reactions ofα-bromoketone intermediate with various nucleophiles containing oxygen,nitrogen and sulfur atom.Their cytotoxic activity was also evaluated against five human cancer cell lines in vitro.
基金financially supported by the Drug Innovation Major Project(No.2018ZX09711001-005-012,China)National Key R&D Program of China(No.2018YFC1706403)+1 种基金CAMS Innovation Fund for Medical Sciences(No.2016-I2M-2-002,China)Disciplines construction project(No.201920200802,China)
文摘FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats.In this study,FTY720 or IMMH002 analogues(21-24)were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms.Target compounds were synthesized via a convergent route using the key and optically pure building block 9,which was first synthesized via asymmetrically catalyzed amination.The phosphorylation rates of these analogues in rat or human blood were compared.The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound,whereas compound 23 showed improvements in rats,but not in humans.In pharmacokinetics studies of rats,compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002.Thus,our study not only yielded new compounds with therapeutic potential,but also showed species differences between rats and humans in response to the structural modifications,which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.
