引起细胞微管超稳定的新型抗肿瘤活性物质epothilones的研究进展

epothilones是新近发现的产自纤维堆囊菌的新型大环内酯类化合物,具有与紫杉醇相似的稳定细胞微管的活性.尽管工作开展不久,但由于其良好的特性,已引起广泛关注.本文对epothilones的发酵产生、全化学合成、生物学活性、应用前景等方面已有的研究进展进行了全面综述.

纤维堆囊菌Soce90菌株发酵合成新型抗癌物质epothilones的营养控制

Ｅｐｏｔｈｉｌｏｎｅｓ是从粘细菌纤维堆囊菌（Ｓｏｒａｎｇｉｕｍｃｅｌｕｌｏｓｕｍ）中新分离的一类具有抗肿瘤活性的次级代谢产物。本文研究了影响纤维堆囊菌Ｓｏｃｅ９０菌株合成ｅｐｏｔｈｉｌｏｎｅｓ的条件。结果表明：菌体的生长状态对产物的合成有影响，指数期接种物、低氮高碳培养条件、某些盐离子、氨基酸和乙酸盐对ｅｐｏｔｈｉｌｏｎｅｓ的合成有益。

基因组重排选育Epothilone B高产菌株

以纤维堆囊菌AHB125经过紫外诱变和2%乙酸钠抗性筛选出来的SC4-14和SC4-56为出发菌株,采用基因组重排技术选育Epothilone B高产菌株,并探索该技术在菌种选育中的基本规律。通过4轮基因组重排成功选育出了5株遗传稳定的Epothilone B高产菌株,其中1株重排菌株F4-28 Epothilone B产量达到67.4 mg/L,是原始菌株纤维堆囊菌AHB125 Epothilone B产量的8倍,是两亲本菌株Epothilone B产量的4-5倍,并且F4-28的发酵周期比SC4-56短1 d。因此,基因组重排技术可有效的选育出Epothilone B高产菌株。

新型天然抗癌物质epothilones

综述了近十年来国际上对纤维素堆囊菌所分泌的具有微管蛋白聚合活性的天然抗癌物质 epothilones的发现、结构。

天然抗癌药物Epothilones研究进展

本文综述了近几年来国际上对纤维素堆囊菌分泌的天然抗癌化合物epothilones的研究进展。其中 ,简要介绍了 epothilones的由来、化学结构、合成方法 ,着重介绍了 epothilone与 Taxol在微管聚合特性上的性能比较。

epothilone类构效关系及生物合成、转化的研究进展

epothilone类化合物大多数具有明显的抗肿瘤作用,并且在来源、合成方法、亲水性、抗肿瘤活性和抗肿瘤谱等方面均优于紫杉醇类药物,是一类新型抗肿瘤药物。近年来,对大量epothilone及其类似物进行了生物活性测定及药效学试验,并借助计算机分析,进行三维定量构效关系研究。在大规模发酵条件下,主要得到epothiloneA和B以及C,D,E等少量成分,其中epothiloneB和D被普遍认为是目前比较有效的抑瘤剂。这些化合物之间存在着某些生物转化关系,有可能会产生新的活性物质。本文主要叙述了该类化合物的构效关系、生物合成及相关转化的研究进展。

基于响应面法的Epothilone发酵优化

Epothilone是由纤维堆囊菌所产生的一类具有高效抗癌作用的次生代谢物。为了提高Epothilone的产量,在单因素试验的基础上,采用响应面法建立了Epothilone发酵培养基和培养条件的二阶数学模型,并验证了模型的有效性;筛选出了3个影响纤维堆囊菌发酵生产Epothilone的主要因素:转速、初始pH值和培养温度;确定了优化的发酵条件:转速180r/min、初始pH值7.8、马铃薯淀粉20g/L、酵母膏10g/L、EDTA-Na-Fe8mg/L、温度29℃、接种量10%。

新型抗肿瘤药物Epothilones的电子结构研究

采用量子化学和分子力学方法寻找一类新型促微管蛋白聚合的大环内酯类抗肿瘤药(Epothilones)的优势构象并进行定量构效关系的研究。通过相关性分析得知,分子的偶极矩和核-核排斥能对分子的活性差异性有显著的影响,可以通过改变C12和C15侧链来改变分子的偶极矩从而提高Epothilones的生物活性。此外,C7上的O原子和C15侧链噻唑基团上的N原子的负电荷增加,对Epothilones的生物活性的增大有利。

Optimization of Fermentation Medium for Epothilones Production with Sequential Statistical Approach

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.

Mechanisms responsible for the inhibitory effects of epothilone B on scar formation after spinal cord injury

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.

Studies of the Total Synthesis of Epothilone B and D: A Facile Synthesis of C7-C14 and C15-C21 Fragments

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.

Efficacy of epothilones in central nervous system trauma treatment:what has age got to do with it?

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.

Effects of epothilone Don microtubule degradation and delayed neuronal death in the hippocampus following transient global ischemia

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.

Synthesis of the C_(11-16)+C_(27) Segment of Epothilone A

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.

Four natural epothilone derivatives isolated from Sorangium cellulosum strain So0157-2

Four natural epothilone analogues, including two 14-membered epothilones L （1）, L1 （2） and two epoxide opened epothilones A （3） and B （4）, were isolated from the extract of fermentation adsorber resin of Sorangium cellulosum strain So0157-2. Their structures were elucidated on the basis of comprehensive NMR and MS data. They are all isolated from the wild type S. cellulosum strain So0157-2 as natural products for the first time.

产Epothilone B纤维堆囊菌的选育与发酵优化

目的:获得高产Epothilone B菌株和最佳营养条件及发酵条件。方法:采用紫外线照射的方法对实验室保存的1株纤纤堆囊菌AHB125进行诱变处理,并采用单因素和正交实验优化培养基中的碳源、氮源和发酵条件。结果:经诱变后获得1株遗传性能稳定变异菌株(SC4-56),Epothilone B产量为14.6mg/L,比初始菌株高195%;该菌株最佳碳源和氮源为6%玉米淀粉和3%蛋白胨,产量分别为20.5和21.8 mg/L;最佳发酵条件为:转速160r/min,温度32℃,接种量8%(V/V),装液量90 mL/500mL,优化后经验证实验,Epothilone B达28.24 mg/L。结论:获得了1株高产量变异菌株,并确定了最佳生产条件。

Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate,BMS-753493,in CD2F1 mice after systemic administration

To assess targeting of an epothilone folate conjugate(BMS-753493) to the folate receptor(FR)-overexpressed tumor in mice bearing both FRt and FR– tumors,a series of experiments were conducted by quantitative whole-body autoradiography(QWBA) and LC–MS/MS following i.v.administration of BMS-753493 or its active moiety,BMS-748285 in mice bearing FRt(98M109) and FR–(M109) tumors.QWBA showed [3H]BMS-753493–derived radioactivity was extensively distributed to various tissues.The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors(i.e.,M109 tumors) up to 48 h post dose of [3H]BMS-753493,despite the magnitude of difference between the tumors is relatively small(generally 3 5-fold).The radioactivity level in 98M109 tumors was 2 12-fold of normal tissues except intestine/content at 48 h post dose.No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v.administration of the active epothilone,[3H]BMS-748285.LC–MS/MS measurements demonstrated that the concentrations of BMS-748285,presumably from hydrolysis of the folate conjugate,in 98M109 tumors were greater than those in M109 tumors after i.v.administration of BMS-753493(2–3-fold) whereas no differential uptake in the tumors following BMS-748285 administration.Those data were consistent with radioactivity determinations.Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR overexpressing 98M109 tumors,thereby supporting targeted delivery of cytotoxics through the folate receptor.