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The oxetane ring in taxol 总被引:2,自引:0,他引:2
Wang M Cornett B Nettles J Liotta DC Snyder JP 《The Journal of organic chemistry》2000,65(4):1059-1068
Numerous structure-activity studies combining synthesis and bioassay have been performed for the anti-cancer drug Taxol. The four-membered D-ring, an oxetane, is one of four structural features regarded to be essential for biological activity. This proposition is examined by application of a Taxol-epothilone minireceptor, K(i) estimation for microtubule binding and docking of Taxol analogues into a model of the Taxol-tubulin complex. In this way, we evaluate the two characteristics considered responsible for oxetane function: (1) rigidification of the tetracyclic Taxol core to provide an appropriate framework for presenting the C-2, C-4, C-13 side chains to the microtubule protein and (2) service as a hydrogen-bond acceptor. An energy decomposition analysis for a series of Taxol analogues demonstrates that the oxetane ring clearly operates by both mechanisms. However, a broader analysis of four-membered ring containing compounds, C- and D-seco derivatives, and structures with no oxetane equivalent underscores that the four-membered ring is not necessary for Taxol analogue bioactivity. Other functional groups and ligand-protein binding characteristics are fully capable of delivering Taxol biobehavior as effectively as the oxetane D-ring. This insight may contribute to the design and development of novel anticancer drugs. 相似文献
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Martello LA LaMarche MJ He L Beauchamp TJ Smith AB Horwitz SB 《Chemistry & biology》2001,8(9):843-855
BACKGROUND: During the past decade, Taxol has assumed an important role in cancer chemotherapy. The search for novel compounds with a mechanism of action similar to that of Taxol, but with greater efficacy particularly in Taxol-resistant cells, has led to the isolation of new natural products. One such compound, (+)-discodermolide, although structurally distinct from Taxol, has a similar ability to stabilize microtubules. In addition, (+)-discodermolide is active in Taxol-resistant cell lines that overexpress P-glycoprotein, the multidrug-resistant transporter. Interestingly, (+)-discodermolide demonstrates a profound enhancement of the initiation process of microtubule polymerization compared to Taxol. RESULTS: The synthesis of (+)-discodermolide analogs exploiting our highly efficient, triply convergent approach has permitted structure-activity relationship (SAR) studies. Small changes to the (+)-discodermolide structure resulted in a dramatic decrease in the ability of all four discodermolide analogs to initiate tubulin polymerization. Two of the analogs also demonstrated a decrease in total tubulin polymerization, while a change in the olefin geometry at the C8 position produced a significant decrease in cytotoxic activity. CONCLUSIONS: The availability of (+)-discodermolide and the analogs, and the resultant SAR analysis, have permitted an exploration of the similarities and differences between (+)-discodermolide and Taxol. Docking of the X-ray/solution structure of (+)-discodermolide into the Taxol binding site of beta-tubulin revealed two possible binding modes (models I and II). The preferred pharmacophore model (I), in which the C19 side chain of (+)-discodermolide matches with the C2 benzoyl group of Taxol and the delta-lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis. 相似文献
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以环烯醚萜类化合物龙胆苦苷为合成模块,利用拟单萜吲哚生物碱的仿生合成途径和组合化学的研究思路,与色胺类衍生物(吲哚结构的活性单元片段)通过缩合反应,首次合成了23个二吲哚甲烷类拟单萜吲哚生物碱类似物。利用核磁共振波谱(NMR)和高分辨质谱(HRMS)等谱学手段对合成化合物的结构进行了表征,并初步评价了其抗肿瘤活性和逆转耐药活性。活性结果表明,化合物4i脱掉糖基保护基后的化合物5i对3种肿瘤细胞系(TE-1,CAL-62和FaDu)的抑制作用强于阳性对照盐酸阿霉素(Dox)。通过与紫杉醇的联合用药,发现部分化合物如4m、4n、4o、4r等能够有效降低人肺癌细胞紫杉醇耐药株A549/Taxol对紫杉醇的耐药性,具有良好的逆转耐药潜力。 相似文献
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In recent years, β-amino acids and their derivatives have attracted considerable attention due to their occurrence in biologically active natural products, such as dolastatins,cyclohexylnorstatine and Taxol. β-Amino acids also find application in the synthesis of β-lactams,piperidines, indolizidines. Moreover, the peptides consisting of β-amino acids, the so-called β-peptides, have been extensively studied recently. Consequently, considerable efforts have been directed to the synthesis of β-amino acids and their derivatives1. In particular, stereoselective synthesis of β-amino acids has been a challenging project, and there are only limited methods available. In this presentation, we report our efforts in this area. 相似文献
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[reaction: see text] The enantioselective synthesis of the Taxol CD ring unit has been achieved starting from an enantiopure building block, the enantiomer of those previously utilized in the synthesis of the A ring unit. The key features of the present synthesis are astute use of both enantiomers of the same building block and complete control in the construction of five consecutive chiral centers. 相似文献
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T Ishikawa R Kadoya M Arai H Takahashi Y Kaisi T Mizuta K Yoshikai S Saito 《The Journal of organic chemistry》2001,66(24):8000-8009
We have revisited the traditional consecutive Michael-Claisen [3 + 3] process (MC-[3 + 3]) promising the synthesis of a cyclohexane-1,3-dione derivatives from nonactivated simple ketones and enoates and evaluated its potential in modern organic synthesis. Twenty to thirty examples were demonstrated to be effective. The reactions exhibited remarkable regioselectivity with the Michael addition proceeding through nucleophilic attack by the more hindered site of the ketones without exception. The subsequent Claisen condensation resulted in the formation of carbon-carbon bonds between less hindered site of the ketones and acyl carbon of the enoates. The MC-[3 + 3] process described is useful for the synthesis of Taxol A-ring synthons in multigram quantities and for the synthesis of other six-membered carbocyclic compounds. A number of control experiments have been conducted to provide strong support for the mechanism of this MC-[3 + 3]. 相似文献
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The synthesis of taxa-4(20),11(12)-diene-2alpha,5alpha-diol is described. An improved procedure for the intramolecular Diels-Alder cycloaddition previously reported in our synthesis of taxa-4(5), 11(12)-diene has been utilized to prepare a taxoid with oxygenation in the B and C rings. It has been established previously that taxa-4(20),11(12)-dien-5alpha-ol is the first oxygenated intermediate on the biosynthetic pathway to Taxol. Taxa-4(20), 11(12)-diene-2alpha,5alpha-diol (5), which has been observed in a biosynthetic conversion, is a potential candidate as the second oxygenated intermediate on the Taxol biosynthetic pathway, has been prepared to probe the intermediacy of this substance. 相似文献
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Taxol is one of the most important anti-cancer drugs. The interaction between different variants of Taxol, by altering one of its chiral centers at a time, with β-tubulin protein has been investigated. To achieve such goal, docking and molecular dynamics (MD) simulation studies have been performed. In docking studies, the preferred conformers have been selected to further study by MD method based on the binding energies reported by the AutoDock program. The best result of docking study which shows the highest affinity between ligand and protein has been used as the starting point of the MD simulations. All of the complexes have shown acceptable stability during the simulation process, based on the RMSDs of the backbone of the protein structure. Finally, MM-GBSA calculations have been carried out to select the best ligand, considering the binding energy criteria. The results predict that two of the structures have better affinity toward the mentioned protein, in comparison with Taxol. Three of the structures have affinity similar to that of the Taxol toward the β-tubulin. 相似文献
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Dr. Changxia Yuan Prof. Dr. Phil S. Baran 《Angewandte Chemie (International ed. in English)》2016,55(29):8280-8284
In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol ( 1 ) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E ( 2 ) and taxabaccatin III ( 3 ), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two‐phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox‐isomerization to set the key trans‐diol present in 2 and 3 . This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi‐synthesis. 相似文献
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Changxia Yuan Yehua Jin Nathan C. Wilde Phil S. Baran 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2016,128(29):8420-8424
In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol ( 1 ) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E ( 2 ) and taxabaccatin III ( 3 ), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two‐phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox‐isomerization to set the key trans‐diol present in 2 and 3 . This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi‐synthesis. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(24):7031-7035
The anticancer drug paclitaxel (Taxol) exhibits paradoxical and poorly understood effects against slow‐growing tumors. To investigate its biological activity, fluorophores such as Oregon Green have been linked to this drug. However, this modification increases its polarity by approximately 1000‐fold and reduces the toxicity of Taxol towards cancer cell lines by over 200‐fold. To construct more drug‐like fluorescent probes suitable for imaging by confocal microscopy and analysis by flow cytometry, we synthesized derivatives of Taxol linked to the drug‐like fluorophore Pacific Blue (PB). We found that PB‐Gly‐Taxol bound the target protein β‐tubulin with both high affinity in vitro and high specificity in living cells, exhibited substantial cytotoxicity towards HeLa cells, and was a highly sensitive substrate of the multidrug resistance transporter P‐glycoprotein (P‐gp). 相似文献
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《Electroanalysis》2004,16(8):688-690
We report the development and characterization of a biosensor for sensitive and rapid determination of the anticancer agent Taxol (paclitaxel). The sensor is based on the interaction of Taxol with its receptor protein tubulin in conjunction with the separation‐free immunosensor technique of enzyme channeling. The sensor system consisted of a three electrode electrochemical cell containing a graphite carbon electrode modified with glucose oxidase and tubulin as working electrode poised at +40 mV (vs. Ag/AgCl). Addition of Taxol, horseradish peroxidase labeled Taxol, glucose and potassium iodide to the cell generated a cathodic current response that was proportional to the concentration of Taxol in the range of 10 to 1 000 pM. 相似文献
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Dr. Molly M. Lee Zhe Gao Prof. Dr. Blake R. Peterson 《Angewandte Chemie (International ed. in English)》2017,56(24):6927-6931
The anticancer drug paclitaxel (Taxol) exhibits paradoxical and poorly understood effects against slow-growing tumors. To investigate its biological activity, fluorophores such as Oregon Green have been linked to this drug. However, this modification increases its polarity by approximately 1000-fold and reduces the toxicity of Taxol towards cancer cell lines by over 200-fold. To construct more drug-like fluorescent probes suitable for imaging by confocal microscopy and analysis by flow cytometry, we synthesized derivatives of Taxol linked to the drug-like fluorophore Pacific Blue (PB). We found that PB-Gly-Taxol bound the target protein β-tubulin with both high affinity in vitro and high specificity in living cells, exhibited substantial cytotoxicity towards HeLa cells, and was a highly sensitive substrate of the multidrug resistance transporter P-glycoprotein (P-gp). 相似文献
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The feasibility of the title reaction has been pursued for the purpose of advancing a concise total synthesis of Taxol. Of the two closely related series examined, the first featured an exo-methylene group at C4. The second consisted of an alpha-epoxide at that site. Strikingly, the olefinic construct proved inert to attempted alpha-ketol rearrangement. In contrast, the oxiranyl derivative isomerized smoothly. The reaction sequence associated with arrival at taxane 18 is short (15 steps from a D-camphor derivative) and notably efficient. The thermodynamic issues that are raised by this investigation have been clarified by an assessment of molecular mechanics-derived (MM3) steric energy calculations. 相似文献
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Bernd Schfer 《Chemie in Unserer Zeit》2011,45(1):32-46
Cancer diseases are known since antiquity. The discovery of Paclitaxel and the development of Taxol(r) is a milestone in natural product synthesis and in cancer research as well. Immediately after the discovery of its unique pharmacological properties, the clinical supply with material of such a highly sophisticated molecular structure became a serious issue. Over the years, numerous total syntheses from prestigious research groups appeared in the literature but from the early beginnings the clinical demand was covered first by extraction of the yew bark and later on by partial synthesis. Since the 1990s Paclitaxel is also produced by plant cell fermentation. 相似文献
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抗癌药物紫杉醇的制备、抗癌机理和应用前景 总被引:6,自引:0,他引:6
紫杉醇具有显著的抗癌活性和独特的作用机理,现主要用于治疗晚期乳腺癌和卵巢癌等。紫杉醇分子结构复杂,具有特殊的三环[6+8+6]碳架和桥头双键以及众多的含氧取代基,其全合成引起国内外许多有机化学家的兴趣。本文简述紫杉醇的制备、抗癌机理和不良反应。 相似文献
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Taxol is the most important member of the clinically useful natural anticancer drug. An endophytic fungus Chaetomella raphigera (strain TAC-15) was isolated from a medicinal plant Terminalia arjuna and screened for its potential in Taxol production. The fungus was identified based on the morphology of the fungal culture
and the characteristics of the spores. This fungus was grown in MID liquid medium and analyzed by chromatographically and
spectrometrically for the presence of Taxol. The amount of Taxol produced by this endophytic fungus was quantified by HPLC
which showed that it produced 79.6 μg/L, and further confirmative analyses were done by using UV, IR, FAB mass spectroscopy,
and NMR spectroscopy. Thus, the fungus can serve as a potential material for fungus engineering to improve the production
of Taxol. 相似文献