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1.
《Chemistry & biology》1998,5(7):365-372
Background: The epothilones are natural substances that are potently cytotoxic, having an almost identical mode of action to TaxolTM as tubulin-polymerization abd microtubule-stabilizing agents. The development of detailed structure-activity relationships for these compounds and the further elucidation of their mechanism of action is of high priority.Results: The chemical synthesis of the C12,13-cyclopropyl analog of epothilone A and its C12,13-trans-diastereoisomer has been accomplished. These compounds and several other epothilone analogs have been screened for their ability to induce tubulin polymerization and death of a number of tumor cells. Several interesting structure-activity trends within this family of compounds were identified.Conclusions: The results of the biological tests conducted in this study have demonstrated that, although a number of positions on the epothilone skeleton are amenable to modification without significant loss of biological activity, the replacement of the epoxide moiety of epothilone A with a cyclopropyl group leads to total loss of activity. 相似文献
2.
Nicolaou KC Namoto K Ritzén A Ulven T Shoji M Li J D'Amico G Liotta D French CT Wartmann M Altmann KH Giannakakou P 《Journal of the American Chemical Society》2001,123(38):9313-9323
The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction to construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC(50) = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold. 相似文献
3.
Nicolaou KC Hepworth D King NP Finlay MR Scarpelli R Pereira MM Bollbuck B Bigot A Werschkun B Winssinger N 《Chemistry (Weinheim an der Bergstrasse, Germany)》2000,6(15):2783-2800
The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level of efficiency and stereoselectivity. This strategy has been applied to the construction of vinyl iodide 19 which served as a common intermediate for the synthesis of a series of natural and designed epothilones including an epothilone B10 (3), epothilone F (5), 16-desmethylepothilone B (14), pyridine epothilones 57a-57g, dimeric epothilones 59 and 61, and benzenoid epothilones 63a-63g. 相似文献
4.
Lee CB Chou TC Zhang XG Wang ZG Kuduk SD Chappell MD Stachel SJ Danishefsky SJ 《The Journal of organic chemistry》2000,65(20):6525-6533
A new epothilone analogue, 12,13-desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), was synthesized and evaluated for antitumor potential. A convergent strategy employed for the semipractical synthesis of 12,13-desoxyepothilone B (dEpoB) has been utilized to yield an amount of dEpoF sufficient for relevant biological studies. The results from an in vitro assay reveal that this new analogue is highly active against various tumor cell lines with a potency comparable to that of dEpoB. In particular, the growth of resistant tumor cells is inhibited by dEpoF at concentrations where paclitaxel (Taxol) is basically ineffective. A preliminary assessment of its in vivo activity is also promising. The new analogue, containing an additional hydroxyl group at C21, exhibits advantages over other epothilones in terms of water solubility, and can serve as a readily functionalizable handle to produce other useful compounds for pertinent biological studies. 相似文献
5.
Johnson J Kim SH Bifano M DiMarco J Fairchild C Gougoutas J Lee F Long B Tokarski J Vite G 《Organic letters》2000,2(11):1537-1540
[structure--see text] A semisynthetic route to epothilone cyclopropanes from epothilones A and B is described. Of significance, the deoxygenation of the 12, 13-epoxide to give the corresponding olefin was achieved with high efficiency. The title compounds (8, 9) were active in both tubulin polymerization and cytotoxicity assays, which is in direct contrast to a previously published report. These results provide further evidence that the role of the 12,13-epoxide of epothilones is largely conformational and argue against some of the current pharmacophore models. 相似文献
6.
Christian N. Kuzniewski Simon Glauser Fabienne Z. Gaugaz Raphael Schiess Javier Rodríguez‐Salarichs Stefan Vetterli Oliver P. Horlacher Jürg Gertsch Mariano Redondo‐Horcajo Angeles Canales Jesús Jimnez‐Barbero Jos Fernando Díaz Karl‐Heinz Altmann 《Helvetica chimica acta》2019,102(5)
A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones. 相似文献
7.
P. I. Zakharov V. P. Zvolinskii S. G. Poshivalov V. G. Pleshakov T. S. Seitembetov 《Chemistry of Heterocyclic Compounds》1979,15(5):535-540
The mass spectra of 15 compounds of the 4-azaphenanthrene series and their deutero analogs with bulky R substituents (R=-CCPh, -CH=CHPh, CHBr-CHBrPh,-CH=CHC6H4OCH3-p, -COOH, -COOC2H5, and -CONHNH2) in the ortho position relative to the nitrogen atom were studied. An intense [M-H]+ ion peak, the appearance of which is evidently due to a process involving cyclization of the carbon atom of the side chain with the nitrogen atom, is formed in the fragmentation of the styryl derivatives. The fragmentation of the compounds with a methyl group in the ortho position relative to the styryl grouping is accompanied by the formation of an intense [M-Ph]+ ion peak. An ortho effect of the carboxyl and carbethoxy groups adjacent to the methyl substituent is observed in the mass spectra of the investigated compounds. The data obtained make it possible to establish the structures of bulky substituents in the ortho position relative to the ring nitrogen atom and the position of the methyl group in the pyridine ring of monomethylated azaphenahthrenes.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 659–665, May, 1979. 相似文献
8.
Kawakami K Takahashi H Ohki H Kimura K Miyauchi S Miyauchi R Takemura M 《Chemical & pharmaceutical bulletin》2000,48(11):1667-1672
A series of 8-methoxyquinolones bearing 3-amino-4-methylpyrrolidines or 3-amino-4-fluoromethylpyrrolidines at the C-7 position was synthesized and their physicochemical and biological properties were evaluated. All of the compounds synthesized showed more potent activity than LVFX (3) against both gram-positive and negative bacteria. Increases in lipophilicity of these compounds had desirable effects on their potency of single intravenous toxicity and pharmacokinetic profiles in animals. Among the compounds synthesized, 1-fluorocyclopropyl derivatives 17 and 20, and 7-(cis-3-amino-4-fluoromethylpyrrolidinyl) derivative 19 (DC-756h) showed negative responses in the micronucleus test in mice while 1-cyclopropyl-7-(3-aminopyrrolidinyl) derivative 16 showed a positive response. These results suggested that the introduction of a fluorine atom into the 3-aminopyrrolidinyl substituent resulted in favorable influence on genetic toxicity as well as into the N-1 cyclopropyl substituent. 相似文献
9.
Regueiro-Ren A Borzilleri RM Zheng X Kim SH Johnson JA Fairchild CR Lee FY Long BH Vite GD 《Organic letters》2001,3(17):2693-2696
[reaction: see text]. A series of 12alpha,13alpha-aziridinyl epothilone derivatives were synthesized in an efficient manner from epothilone A. The final semisynthetic route involves a formal double-inversion of stereochemistry at both the C12 and C13 positions. All aziridine analogues were tested for effects on tubulin binding polymerization and cytotoxicity. The results indicate that the aziridine moiety is a viable isosteric replacement for the epoxide in the case of epothilones. 相似文献
10.
Wang JD Jiang N Zhang H Ying LP Wang CX Xiang WS Wu B Wang HB Bai H 《Natural product research》2011,25(18):1707-1712
As a continuous work to find more epothilone congeners produced by the epothilones A and B producing Sorangium cellulosum strain So0157-2 in the large-scale fermentation (5000?L), we reinvestigated the chemical compositions of the fermentation broth. Consequently, two new epothilone variants (1-2) and one new natural epothilone derivative (3) were isolated from the fermentation broth. Their structures were established as 16-ethyl epothilone B (1), 6-desmethyl-16-hydroxymethyl epothilone C (2) and 20-ethyl epothilone A (3), respectively, by an extensive NMR analysis. 相似文献
11.
12.
B. Mario Pinto Walter A. Szarek T. Bruce Grindley 《Magnetic resonance in chemistry : MRC》1984,22(11):676-692
Analogs of N-acetyl- and N-benzoyl-azacyclohex-2-enes having an oxygen atom, a methylene-d2 group or a carbonyl group in place of the C-4 methylene group have been synthesized. The amide rotational barriers in these compounds have been measured by the total line-shape analysis of variable-temperature 1H NMR spectra. The free energies of activation for both the N-acetyl and N-benzoyl series decrease in the sequence O?CD2 > C?O. The barriers for the first two compounds in each series are similar to those of the corresponding saturated analogs, a result which confirms recent reports that the long accepted barrier-decreasing effect of an α-olefinic substituent on nitrogen is counteracted. Evidence is presented that resonance stabilization of the rotational transition state in the unsaturated compounds still obtains. It is suggested that the introduction of an α-olefinic substituent on nitrogen has a negligible effect on the amide rotational barriers in the cases of the oxygen and methylene-d2 analogs, since any increase in the stabilization of the transition state by resonance is offset by the accompanying decrease in the sp3 character of the nitrogen atom. In cases in which a substituent on the olefinic group can interact directly with the lone pair on nitrogen, for example in the carbonyl analogs, then the resonance stabilization of the transition state is dominant. 相似文献
13.
Conghao Deng 《International journal of quantum chemistry》1985,27(2):233-234
The electron density at the pyridine nitrogen atom and the π-electron density of the pyridine ring were calculated by the CNDO /2-MO method assuming standard bond lengths and angles. The indices were found to correlate with the pKa values of pyridine derivatives and with the electronic substituent constants of the Hammett type. The correlations were best for four-substituted pyridines, making the routine CNDO /2-MO calculations useful for studies of quantitative relations between structure and biological activity of the compounds. 相似文献
14.
Tang L Ward S Chung L Carney JR Li Y Reid R Katz L 《Journal of the American Chemical Society》2004,126(1):46-47
The epothilones, originally isolated from the myxobacterium Sorangium cellulosum, are macrocyclic compounds that are synthesized by a modular polyketide synthase, an enzyme complex composed of six large, multifunctional proteins. The penultimate intermediates in epothilone production, and the products of the PKS-catalyzed reactions, are epothilones D and C, which contain a 12,13-cis-double bond. The 12 and 13 positions of epothilones are generated during the fourth elongation step that is governed by module 4. Module 4 does not contain a dehydratase (DH) domain, which is required for dehydration to create the double bond. A DH domain, present in module 5 and presumed to act in the fifth elongation step at the 10 and 11 positions, was proposed to act as well to generate the 12,13-cis-double bond. Inactivation of the DH domain in module 5 resulted in the production of 10,11-dehydro-13-hydroxyepothilone D as the major product, confirming that DH5 is required for 12,13 dehydration. A mechanistic model based on domain skipping and modular stuttering is presented to explain the basis for the iterative DH5 activity observed. 相似文献
15.
Valeev R. F. Sunagatullina G. R. Loza V. V. Lobov A. N. Miftakhov M. S. 《Russian Journal of Organic Chemistry》2021,57(6):889-904
Russian Journal of Organic Chemistry - A new chiral 10,11-didehydro analog of epothilone D with isosteric substitution in the C15–C3 fragment of natural epothilones has been synthesized. 相似文献
16.
含吡啶环的1,3,4-噁二唑衍生物的合成及生物活性研究 总被引:22,自引:0,他引:22
依据生物电子等排原理,在分子中同时引入吡啶环和1,3,4-噁二唑杂环合成了5-(3-吡啶基或4-吡啶基)-1,3,4-噁二唑2-硫乙酸胺类化合物,用1HNMR,IR,质谱和元素分析对其结构进行了表征.离体试验表明,化合物B1-5小麦赤霉病菌和苹果轮纹病菌的抑制率分别为30%和42%,化合物B1-6对苹果轮纹病菌的抑制率为38%.除草活性实验结果表明,化合物B1-6对油菜和稗草具有较高的抑制作用. 相似文献
17.
A conformationally restrained epothilone A analogue (3) with a short bridge between methyl groups at C6 and C8 was designed and synthesized. Preliminary biological evaluation indicates 3 to be only weakly active (IC50 = 8.5 microM) against the A2780 human ovarian cancer cell line. 相似文献
18.
Schneider TL Walsh CT O'Connor SE 《Journal of the American Chemical Society》2002,124(38):11272-11273
The epothilones, a family of macrolactone natural products produced by the myxobacterial species Sorangium cellulosum, are of current clinical interest as antitumor agents. Inspection of the structure of the epothilones suggests a hybrid polyketide/nonribosomal peptide biosynthetic origin, and the recent sequencing of the epothilone biosynthetic gene cluster has validated this proposal. Here we have examined unnatural substrates with the first two enzymes of the biosynthetic pathway, EpoA and EpoB, to investigate the enzymatic construction of alternate heterocyclic structures and the subsequent elongation of these products by the third enzyme of the pathway, EpoC. The epothilone biosynthetic machinery can utilize serine to install an oxazole in place of a thiazole in the epothilone structure and will tolerate functionalized donor groups from the EpoA-ACP domain to produce epothilone fragments modified at the C21 position. These studies with the early enzymes of the epothilone biosynthesis cluster suggest that combinatorial biosynthesis may be a viable means for producing a variety of epothilone analogues that incorporate diversity into the heterocycle starter unit. 相似文献
19.
Fused Heterocycles: Synthesis and Antitubercular Activity of Novel 6‐Substituted‐2‐(4‐methyl‐2‐substituted phenylthiazol‐5‐yl)H‐imidazo[1,2‐a]pyridine 下载免费PDF全文
Yogita K. Abhale Keshav K. Deshmukh Amit V. Sasane Abhijit P. Chavan Pravin C. Mhaske 《Journal of heterocyclic chemistry》2016,53(1):229-233
A series of 6‐substituted‐2‐(4‐methyl‐2‐substituted phenylthiazol‐5‐yl)H‐imidazo[1,2‐a]pyridine derivatives 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l is described. The antitubercular activity of the synthesized compounds was determined against Mycobacterium smegmatis MC2 155 strain. From the activity result, it was found that the phenyl or 4‐fluorophenyl group at 2 position of thiazole nucleus and bromo substituent at 6 position of imidazo[1,2‐a]pyridine showed good antitubercular activity. 相似文献
20.
The conformation-activity relationships for the biologically active polyketide, epothilone, have been determined. Computer-based molecular modeling and high field NMR techniques have provided the solution preferences for epothilones and. For the C1-C8 polypropionate region, two conformational families, conformers 1 and 2, have been identified as having significant populations in polar and non-polar solvents. In the C11-C15 region, additional flexibility was observed and two local conformations have been identified as important, conformers 3 and 4. Epothilone analogues with altered conformational profiles have been designed and synthesized. Conformational analysis and the results of biological assays have been correlated to provide increased understanding of the biologically active conformation for the epothilone class of natural product. Conformation-activity relationships have been shown to be an important complement to structure-activity data. 相似文献