A sequential statistical approach was applied to optimizing the fermentation medium of epothilones（Epos） production by means of a mutant which was obtained by treating polyangium cellulosum ATCC 15384 with nitrite a...A sequential statistical approach was applied to optimizing the fermentation medium of epothilones（Epos） production by means of a mutant which was obtained by treating polyangium cellulosum ATCC 15384 with nitrite and ultraviolet. The effects of different carbon sources and nitrogen sources on the fermentation medium were tested, and the suitable ones were selected. Then a uniform design was employed to design the experiments. A linear model was developed for identifying the significant components in fermentation medium, while a third degree polynomial model was used for studying the relationship between the concentration of the components in fermentation medium and the yield of Epos（YEPs）. A pattern search method was used for searching the optimum fermentation medium in the test space, which was as follows（g/L）： potassium nitrate 8.00, soybean peptone 17.60, potassium hydrogen phos- phate 1.00, beef extraction 6.46, yeast extraction 1.00, calcium chloride 0.25, sodium chloride 1.00 and ferric chloride 0.02. The optimum fermentation medium was expected to result in a yield of Epos（YEPs） of 2.48 mg/L. The validation experiments with the optimum medium were performed in triplicate and the average yield of Epos was 2.45 mg/L which was 7.78 times higher than that of Epos prepared without optimization.展开更多
Central nervous system injury,specifically traumatic brain and spinal cord injury,can have significant long lasting effects.There are no comprehensive treatments to combat the injury and sequalae of events that occurr...Central nervous system injury,specifically traumatic brain and spinal cord injury,can have significant long lasting effects.There are no comprehensive treatments to combat the injury and sequalae of events that occurring following a central nervous system trauma.Herein we discuss the potential for the epothilone family of microtubule stabilizing agents to improve outcomes following experimentally induced trauma.These drugs,which are able to cross the blood-brain barrier,may hold great promise for the treatment of central nervous system trauma and the current literature presents the extensive range of beneficial effects these drugs may have following trauma in animal models.Importantly,the effect of the epothilones can vary and our most recent contributions to this field indicate that the efficacy of epothilones following traumatic brain injury is dependent upon the age of the animals.Therefore,we present a case for a greater emphasis to be placed upon age when using an intervention aimed at neural regeneration and highlight the importance of tailoring the therapeutic regime in the clinic to the age of the patient to promote improved patient outcomes.展开更多
Epothilones belong to a class of novel microtubule stabilizing and anti-mitotic agents, which have a paclitaxel-like mechanism of action. A three-dimensional quantitative structure-activity relationship （3D-QSAR） mo...Epothilones belong to a class of novel microtubule stabilizing and anti-mitotic agents, which have a paclitaxel-like mechanism of action. A three-dimensional quantitative structure-activity relationship （3D-QSAR） model was built for epothilones by the method of comparative molecular field analysis （CoMFA） combined with the flexible docking technology. The docking CoMFA model gave a good cross-validated value of q2=0.784 with an optimized component of 6 and the conventional correlation coefficient of r^2=0.985. The statistical results show that the model has good ability to predict the activity of the studied compounds. At last, the docking CoMFA model was analyzed through contour maps complemented with MOLCAD-generated active site potential surface in the α,β-tubulin receptor, which can provide important information for the structure-based drug design.展开更多
Scar formation after spinal cord injury is regarded as an obstacle to axonal regeneration and functional recovery.Epothilone B provides moderate microtubule stabilization and is mainly used for anti-tumor therapy.It a...Scar formation after spinal cord injury is regarded as an obstacle to axonal regeneration and functional recovery.Epothilone B provides moderate microtubule stabilization and is mainly used for anti-tumor therapy.It also reduces scar tissue formation and promotes axonal regeneration after spinal cord injury.The aim of the present study was to investigate the effect and mechanism of the microtubule-stabilizing reagent epothilone B in decreasing fibrotic scarring through its action on pericytes after spinal cord injury.A rat model of spinal cord injury was established via dorsal complete transection at the T10 vertebra.The rats received an intraperitoneal injection of epothilone B（0.75 mg/kg） at 1 and 15 days post-injury in the epothilone B group or normal saline in the vehicle group.Neuron-glial antigen 2,platelet-derived growth factor receptor β,and fibronectin protein expression were dramatically lower in the epothilone B group than in the vehicle group,but β-tubulin protein expression was greater.Glial fibrillary acidic protein at the injury site was not affected by epothilone B treatment.The Basso,Beattie,and Bresnahan locomotor scores were significantly higher in the epothilone B group than in the vehicle group.The results of this study demonstrated that epothilone B reduced the number of pericytes,inhibited extracellular matrix formation,and suppressed scar formation after spinal cord injury.展开更多
A mild and highly efficient synthesis of C7-C14 and C15-C21 fragments of epothilone B and D is described in which racemic C7-C14 fragment is prepared from nerol through four steps, and C15-C21 fragment is obtained fro...A mild and highly efficient synthesis of C7-C14 and C15-C21 fragments of epothilone B and D is described in which racemic C7-C14 fragment is prepared from nerol through four steps, and C15-C21 fragment is obtained from 1, 3-dichloroacetone, thioacetamide and propionaldehyde.展开更多
Disruption of microtubule cytoskeleton plays an important role during the evolution of brain damage after transient cerebral ischemia.However,it is still unclear whether microtubule-stabilizing drugs such asepothilone...Disruption of microtubule cytoskeleton plays an important role during the evolution of brain damage after transient cerebral ischemia.However,it is still unclear whether microtubule-stabilizing drugs such asepothilone D(EpoD)have a neuroprotective action against the ischemia-induced brain injury.展开更多
A chiral synthesis of the C11-16+C27 segment of epomilone A is described using inexpensive L-(-)-malic acid as staring materinal and using Sharpless asymmetric epoxidahon for introduction of the desired 12, 13 epoxide.
基金Supported by the Science Technology Development Project of Jilin Province,China(No.20020503-2)
文摘A sequential statistical approach was applied to optimizing the fermentation medium of epothilones（Epos） production by means of a mutant which was obtained by treating polyangium cellulosum ATCC 15384 with nitrite and ultraviolet. The effects of different carbon sources and nitrogen sources on the fermentation medium were tested, and the suitable ones were selected. Then a uniform design was employed to design the experiments. A linear model was developed for identifying the significant components in fermentation medium, while a third degree polynomial model was used for studying the relationship between the concentration of the components in fermentation medium and the yield of Epos（YEPs）. A pattern search method was used for searching the optimum fermentation medium in the test space, which was as follows（g/L）： potassium nitrate 8.00, soybean peptone 17.60, potassium hydrogen phos- phate 1.00, beef extraction 6.46, yeast extraction 1.00, calcium chloride 0.25, sodium chloride 1.00 and ferric chloride 0.02. The optimum fermentation medium was expected to result in a yield of Epos（YEPs） of 2.48 mg/L. The validation experiments with the optimum medium were performed in triplicate and the average yield of Epos was 2.45 mg/L which was 7.78 times higher than that of Epos prepared without optimization.
文摘Central nervous system injury,specifically traumatic brain and spinal cord injury,can have significant long lasting effects.There are no comprehensive treatments to combat the injury and sequalae of events that occurring following a central nervous system trauma.Herein we discuss the potential for the epothilone family of microtubule stabilizing agents to improve outcomes following experimentally induced trauma.These drugs,which are able to cross the blood-brain barrier,may hold great promise for the treatment of central nervous system trauma and the current literature presents the extensive range of beneficial effects these drugs may have following trauma in animal models.Importantly,the effect of the epothilones can vary and our most recent contributions to this field indicate that the efficacy of epothilones following traumatic brain injury is dependent upon the age of the animals.Therefore,we present a case for a greater emphasis to be placed upon age when using an intervention aimed at neural regeneration and highlight the importance of tailoring the therapeutic regime in the clinic to the age of the patient to promote improved patient outcomes.
文摘Epothilones belong to a class of novel microtubule stabilizing and anti-mitotic agents, which have a paclitaxel-like mechanism of action. A three-dimensional quantitative structure-activity relationship （3D-QSAR） model was built for epothilones by the method of comparative molecular field analysis （CoMFA） combined with the flexible docking technology. The docking CoMFA model gave a good cross-validated value of q2=0.784 with an optimized component of 6 and the conventional correlation coefficient of r^2=0.985. The statistical results show that the model has good ability to predict the activity of the studied compounds. At last, the docking CoMFA model was analyzed through contour maps complemented with MOLCAD-generated active site potential surface in the α,β-tubulin receptor, which can provide important information for the structure-based drug design.
基金supported by a grant from the Science and Technology Developing Program of Shandong Provincial Government of China,No.2010GSF10254a grant from the Medical and Health Science and Technology Plan Project of Shandong Province of China,No.2015WS0504
文摘Scar formation after spinal cord injury is regarded as an obstacle to axonal regeneration and functional recovery.Epothilone B provides moderate microtubule stabilization and is mainly used for anti-tumor therapy.It also reduces scar tissue formation and promotes axonal regeneration after spinal cord injury.The aim of the present study was to investigate the effect and mechanism of the microtubule-stabilizing reagent epothilone B in decreasing fibrotic scarring through its action on pericytes after spinal cord injury.A rat model of spinal cord injury was established via dorsal complete transection at the T10 vertebra.The rats received an intraperitoneal injection of epothilone B（0.75 mg/kg） at 1 and 15 days post-injury in the epothilone B group or normal saline in the vehicle group.Neuron-glial antigen 2,platelet-derived growth factor receptor β,and fibronectin protein expression were dramatically lower in the epothilone B group than in the vehicle group,but β-tubulin protein expression was greater.Glial fibrillary acidic protein at the injury site was not affected by epothilone B treatment.The Basso,Beattie,and Bresnahan locomotor scores were significantly higher in the epothilone B group than in the vehicle group.The results of this study demonstrated that epothilone B reduced the number of pericytes,inhibited extracellular matrix formation,and suppressed scar formation after spinal cord injury.
基金the National Natural Science Foundation of China (No.20214),Ministry of Education Natural Science Foundation and Education Commission of Hubei Province
文摘A mild and highly efficient synthesis of C7-C14 and C15-C21 fragments of epothilone B and D is described in which racemic C7-C14 fragment is prepared from nerol through four steps, and C15-C21 fragment is obtained from 1, 3-dichloroacetone, thioacetamide and propionaldehyde.
文摘Disruption of microtubule cytoskeleton plays an important role during the evolution of brain damage after transient cerebral ischemia.However,it is still unclear whether microtubule-stabilizing drugs such asepothilone D(EpoD)have a neuroprotective action against the ischemia-induced brain injury.
文摘A chiral synthesis of the C11-16+C27 segment of epomilone A is described using inexpensive L-(-)-malic acid as staring materinal and using Sharpless asymmetric epoxidahon for introduction of the desired 12, 13 epoxide.
