Combretastatin A—4膦酸酯二钠盐的合成

以3，4，5-三甲氧基苄醇为起始原料，经溴代、成膦盐，与经硅醚保护的异香草醛进行Witting反应、脱硅醚保护、磷酸酯化、脱保护、成盐得combretastatin A-4膦酸酯二钠盐，总收率32%（以3计）。     

水溶性木犀草素衍生物的半合成

目的:探索水溶性木犀草素衍生物的半合成方法。方法:试图以木犀草素成酚钠后和卤代物进行亲核取代反应,分别在木犀草素7-位引入羧甲基,然后制成了钠盐,达到增加水溶性。结果:通过新的合成路线合成了鲜见报道的化合物。结论:在保留黄酮类化合物生物活性部位的前提下,在木犀草素7-位引入羧甲基,可以制备水溶性羧甲基木犀草素钠盐。     

临床开发中的新药——抗癌药物Combretastatin A4及其类似物

目前，微管蛋白结合剂应为临床应用最为有效的一类抗癌药物。一般是通过对微管的解聚或稳定作用而发挥其抗癌功效。微管是细胞的重要成分，构成有丝分裂器，关系到细胞运动、附着和胞内转运。长春碱类药物，尤其是长春新碱和长春碱已在临床上应用多年，近来又发现长春瑞宾可用于治疗乳腺癌，而该类新药长春氟宁（vinflunine）也已进入临床开发阶段，这类药物为抗有丝分裂剂，可抑制有丝分裂组装。此外，另一临床活性药物紫杉醇则是通过促进形成稳定的非功能性微管而发挥抗癌作用，所以应用具有完全不同作用机制的药物干预微管蛋白同样能有效治疗癌症。然而，现有的这些药物虽具临床活性，但缺乏对晚期癌症病人的疗效，且有损正常组织。近年来，从非洲灌木柳（Combretum caffrum）树皮中分离得到的一种多羟基二苯乙烯类天然化合物combretastatins备受关注，其中由Oxigene公司进一步临床开发的combretastatin A4已取得可喜进展。     

槲皮素水溶性衍生物的制备及生物活性

槲皮素（ｑｕｅｒｃｅｔｉｎ；３，３′，４′，５，７ｐｅｎｔａｈｙｄｒｏｘｙｆｌａｖｏｎｅ）是天然的黄酮类化合物，具有抗肿瘤、抗血小板、抗氧化作用，并影响多种酶的活性〔１～４〕．但由于槲皮素不溶于水，难于吸收〔５〕，极大地限制了其生物利用度和体内给药...     

A-失碳甾体新衍生物中间体合成的改进

目的：改进Ａ－失碳甾体新衍生物合成方法。方法：对中间体α－双炔失碳酯（Ｉ）、α－双炔失碳氯乙酸酯（２）、α－双炔失碳－（α－哌嗪基）－乙酸酯（３）及１７β羟基－Ａ－失碳－５α－雄甾－２－酮（４）的分离或合成方法进行了改进。结果：使反应步骤缩短,操作简化,收率提高。     

水溶性大黄素衍生物的合成及抗白血病的初步研究

目的 改善大黄素衍生物的水溶性问题,以期得到一些抗白血病活性较好的大黄素衍生物。方法 以大黄素为原料,经过羟基保护、N-溴代丁二酰亚胺(NBS)参与的溴代反应、与叔胺成盐反应制得目标化合物。结果与讨论 合成了11个未见文献报道的大黄素衍生物,其结构经IR、¹H-NMR谱和元素分析确证。化合物 3h 、3i 和 3j 对白血病细胞 K562 和 Jurkat 细胞株有较好的活性。     

紫杉醇水溶性衍生物的研究进展

目的　介绍紫杉醇水溶性衍生物的研究进展。方法　依据国内外的文献资料,讨论提高紫杉醇水溶性的研究成果。结果　紫杉醇的水溶性可以通过物理方法制备成特殊制剂加以改善,也可以通过结构修饰制备水溶性的紫杉醇衍生物来得到提高。结论　改善紫杉醇的水溶性,可有效防止不良反应,成为保证紫杉醇抗肿瘤化学治疗得以继续的关键,是紫杉醇今后的研究方向之一。     

紫杉醇水溶性衍生物的研究进展

目的介绍紫杉醇水溶性衍生物的研究进展。方法依据国内外的文献资料,讨论提高紫杉醇水溶性的研究成果。结果紫杉醇的水溶性可以通过物理方法制备成特殊制剂加以改善,也可以通过结构修饰制备水溶性的紫杉醇衍生物来得到提高。结论改善紫杉醇的水溶性,可有效防止不良反应,成为保证紫杉醇抗肿瘤化学治疗得以继续的关键,是紫杉醇今后的研究方向之一。     

微管蛋白抑制剂Combretastatin A-4类似物的研究进展

微管蛋白在细胞生长、维持形态、信号传导及有丝分裂等过程中,均起着重要的作用。微管蛋白抑制剂是近年来热门的抗肿瘤药物。Combretastatin A-4(CA-4)从南非灌木柳树皮Combretum caffrum树干中提取分离得到的二苯乙烯类化合物,是目前已知微管蛋白抑制剂中活性最强的化合物之一,但是也存在着众多缺陷。近年来围绕提高CA-4水溶性、保持顺式构型等衍生物的设计研究成为了热点。本文就CA-4的结构改造及类似物设计的研究进展进行综述。     

Combretastatin A4磷酸酯二钠在大鼠体内的药物动力学

目的研究前药Combretastatin A4磷酸酯二钠(CA4P)在大鼠体内生成Combretastatin A4(CA4)的药物动力学。方法采用HPLC法测定iv10、20mg·kg-1CA4P后,大鼠体内不同时间点的原药CA4的血药浓度。药-时数据经DAS统计软件拟合处理。结果两个剂量组的CA4在大鼠体内的过程均符合二室模型,t1/2β分别为34.427±2.849、30.076±3.107min;Vd分别为1.402±0.178、1.568±0.131L·kg-1;Cl分别为0.061±0.003、0.058±0.003L·min-·1kg-1;AUC0-t分别为132.393±3.144、291.872±15.555mg·L-·1min。结论静注CA4P后,CA4在大鼠体内以二室模型的规律快速代谢和消除。     

Combretastatin A-4及其类似物构效关系研究进展

Combretastatin A-4(CA-4)是一个天然的秋水仙碱结合位点抑制剂,其突出的生物活性引起人们的高度关注,近年来,不断有结构多样的类似物被发现。这些类似物主要是针对CA-4的A环、B环和顺式双键的结构修饰,其中,以用单原子或环状结构替代顺式双键进而保持A/B环具有合适的空间距离和角度为主。本文对CA-4及其类似物构效关系的研究进行简单概述。     

Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents

The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization, and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41, and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent antiproliferative activity of the series. β-Lactam 41 in particular showed subnanomolar activity in MCF-7 breast cancer cells (IC??= 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumor agents that target tubulin.     

In vitro and in vivo phase II metabolism of combretastatin A-4: Evidence for the formation of a sulphate conjugate metabolite

1. Combretastatin A-4 (CA-4), is a natural compound with a potent tubulin polymerization and cell growth inhibitor properties. For these reasons CA-4 is one of the most potent anti-vascular agents that shows strong cytotoxicity against a variety of human cancer cells, including multi-drug-resistant cancer cell lines. In order to complete the knowledge of metabolic fate of CA-4, the in vitro and in vivo phase II metabolism was investigated.

2. Both in incubation with rat and human liver S9 preparation in the presence of 39-phosphoadenosine-5´-phosphosulfate (PAPS) as a cofactor the formation of a previously no reported sulphate metabolite was demonstrated through liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) data and comparison with a synthetic reference sample.

3. In incubation of CA-4 using rat and human liver microsomes, the formation of CA-4 glucuronide was observed and chromatographic and mass spectral properties of the metabolite were achieved and compared with those of a synthetic reference sample.

4. Incubation of CA-4 with rat and human liver S9 preparation in the presence of uridine-5´-diphosphoglucuronic acid trisodium salt (UDPGA) and an β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-regenerating system as cofactors resulted in the formation of glucuronides arising from phase I CA-4 metabolites.

5. When CA-4 was administered intraperitoneally to rat at a dose of 30 mg kg^?1, both glucuronide and sulphate metabolites were observed in LC-ESI-MS-MS chromatograms and their mass spectral data were identical to those obtained from synthetic standards.

     

Synthesis and evaluation of 1,5-disubstituted tetrazoles as rigid analogues of combretastatin A-4 with potent antiproliferative and antitumor activity

Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.     

Synthesis and antiprotozoal activity of 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs of combretastatin A-4

Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a?Cj, 6a?Ce, and 7a?Cc) of combretastatin A-4 were synthesized with the objective of discovering compounds capable of controlling the growth of Trypanosoma?lewisii, Leishmania?tarantole, Plasmodium?falciparum, and Giardia?lamblia. Even though the target compounds demonstrated differential cytotoxicity against mammalian cancer cells, with IC₅₀ values ranging from 0.5 to >100???M, the range of activity against Trypanosoma, Leishmania, and Plasmodium, and to a good extent for Giardia, was narrow. The IC₅₀ values of ??active?? compounds against the parasites ranged from about 10???? to slightly greater than 50???M. Specifically, compounds 5a, 5g, 5h, 6c, 7a, and 7c were not cytotoxic against mammalian cancer cells (IC₅₀?>?100???M) but showed good activity against the parasites, except Giardia (e.g., compounds 6c and 7a), suggesting that these compounds may act in a similar mechanism in parasites. Compounds 5f and 6b were previously shown to promote microtubule depolymerization in mammalian cells.     

Novel A-ring and B-ring modified combretastatin A-4 (CA-4) analogues endowed with interesting cytotoxic activity

A novel class of combretastatins, modified at A-ring or both A- and B-rings, mainly by replacement with benzofuran or benzo[b]thiophene, were synthesized. The new heterocombretastatins showed good cytotoxic activity on BMEC and H-460 cell lines. The aminocombretastatin 9f potently inhibits cell growth of BMEC and combretastatin-resistant HT-29 cell lines, with potential interest to treat colon carcinoma. Heterocombretastatins 9a,b inhibit tubulin polymerization similarly to CA-4 by having a binding to colchicine site five times stronger.     

Synthesis and biological activity of fluorinated combretastatin analogues

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.     

Developments of combretastatin A-4 derivatives as anticancer agents

Tubulin protein is one of several members of a small family of globular proteins. It offers a potential target for anticancer drug design and development. Combretastatin A-4 (CA-4) is a potent anticancer and antiangiogenesis natural substance isolated from Combretum caffrum. Modifications on the CA-4 structure have led to a great number of novel CA-4 derivatives as potent tubulin inhibitors and high cytotoxic anticancer agents is becoming an interesting field, leading to a breakthrough in the treatment of cancer. In this review, the recent developments of novel CA-4 derivatives via the modifications on the A- and B-ring and the double bond as anticancer agents are discussed.