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Total synthesis of epothilone A - ScienceDirect

The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1–C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.

A convergent total synthesis of epothilone A is described
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AB - Unusually promising profiles of antitumor activity are displayed by 26-trifluoro-(E)-9,10-dehydro-dEpoB (1), the design and practical total synthesis of which is described. This compound promotes tumor shrinkage and disappearance in human xenografts in nude mice at well-tolerated doses, with complete remission for over two months and early rapid recovery of body weight to the pretreatment control levels.

An Efficient Total Synthesis of (−)-Epothilone B - …

T1 - Design and Total Synthesis of a Superior Family of Epothilone Analogues, which Eliminate Xenograft Tumors to a Nonrelapsable State
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AB - A concise modular laboratory construction of the epothilone class of promising antitumor agents has been accomplished. For the first time in the epothilone area, the new synthesis exploits the power of ring-closing olefin metathesis (RCM) in a stereospecific way. Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by complete lack of stereocontrol in the generation of the desired 12,13-olefin geometry in the products. The isolation of epothilone 490 (3) prompted us to reevaluate the utility of the RCM procedure for fashioning the 10,11-olefin, with the Z-12,13-olefin geometry already in place. Olefin metathesis of the triene substrate 12 afforded the product diene macrolide in stereoselective fashion. For purposes of greater synthetic convergency, the C3-(S)-alcohol was fashioned late in the synthesis, using chiral titanium-mediated aldol conditions with the entire O-alkyl fragment as a C15 acetate as the enolate component. Examination of the effects of protecting groups on the RCM process showed that deprotection of the C7 alcohol has a beneficial effect on the reaction yield. Performing the RCM as the last synthetic step in the sequence afforded a 64% yield of only the desired E-olefin. Selective diimide reduction of the new 10,11-olefin yielded 12,13-desoxyepothilone B, our current clinical candidate, demonstrating the utility of this new RCM-reduction protocol in efficiently generating the epothilone framework. Furthermore, the new olefin was selectively funtionalized to demonstrate the advantage conferred by this route for the construction of new analogues for SAR studies, in cytoxicity and microtubule affinity screens. Also described is the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promising in vitro data. This disappointing outcome was traced to unfavorable pharmacokinetic features of the drug in murine plasma. By the pharmacokinetic criteria, the prognosis for the effectiveness of 3 in humans is, in principle, much more promising.

N2 - A concise modular laboratory construction of the epothilone class of promising antitumor agents has been accomplished. For the first time in the epothilone area, the new synthesis exploits the power of ring-closing olefin metathesis (RCM) in a stereospecific way. Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by complete lack of stereocontrol in the generation of the desired 12,13-olefin geometry in the products. The isolation of epothilone 490 (3) prompted us to reevaluate the utility of the RCM procedure for fashioning the 10,11-olefin, with the Z-12,13-olefin geometry already in place. Olefin metathesis of the triene substrate 12 afforded the product diene macrolide in stereoselective fashion. For purposes of greater synthetic convergency, the C3-(S)-alcohol was fashioned late in the synthesis, using chiral titanium-mediated aldol conditions with the entire O-alkyl fragment as a C15 acetate as the enolate component. Examination of the effects of protecting groups on the RCM process showed that deprotection of the C7 alcohol has a beneficial effect on the reaction yield. Performing the RCM as the last synthetic step in the sequence afforded a 64% yield of only the desired E-olefin. Selective diimide reduction of the new 10,11-olefin yielded 12,13-desoxyepothilone B, our current clinical candidate, demonstrating the utility of this new RCM-reduction protocol in efficiently generating the epothilone framework. Furthermore, the new olefin was selectively funtionalized to demonstrate the advantage conferred by this route for the construction of new analogues for SAR studies, in cytoxicity and microtubule affinity screens. Also described is the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promising in vitro data. This disappointing outcome was traced to unfavorable pharmacokinetic features of the drug in murine plasma. By the pharmacokinetic criteria, the prognosis for the effectiveness of 3 in humans is, in principle, much more promising.

Previous article in issue: Total Synthesis of (−)-Epothilone A

A convergent and stereoselective total synthesis of epothilone B (2) is described
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A concise modular laboratory construction of the epothilone class of promising antitumor agents has been accomplished. For the first time in the epothilone area, the new synthesis exploits the power of ring-closing olefin metathesis (RCM) in a stereospecific way. Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by complete lack of stereocontrol in the generation of the desired 12,13-olefin geometry in the products. The isolation of epothilone 490 (3) prompted us to reevaluate the utility of the RCM procedure for fashioning the 10,11-olefin, with the Z-12,13-olefin geometry already in place. Olefin metathesis of the triene substrate 12 afforded the product diene macrolide in stereoselective fashion. For purposes of greater synthetic convergency, the C3-(S)-alcohol was fashioned late in the synthesis, using chiral titanium-mediated aldol conditions with the entire O-alkyl fragment as a C15 acetate as the enolate component. Examination of the effects of protecting groups on the RCM process showed that deprotection of the C7 alcohol has a beneficial effect on the reaction yield. Performing the RCM as the last synthetic step in the sequence afforded a 64% yield of only the desired E-olefin. Selective diimide reduction of the new 10,11-olefin yielded 12,13-desoxyepothilone B, our current clinical candidate, demonstrating the utility of this new RCM-reduction protocol in efficiently generating the epothilone framework. Furthermore, the new olefin was selectively funtionalized to demonstrate the advantage conferred by this route for the construction of new analogues for SAR studies, in cytoxicity and microtubule affinity screens. Also described is the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promising in vitro data. This disappointing outcome was traced to unfavorable pharmacokinetic features of the drug in murine plasma. By the pharmacokinetic criteria, the prognosis for the effectiveness of 3 in humans is, in principle, much more promising.

The epothilones are a new class of cytotoxic molecules identified as potential drugs. As of September 2008, epothilones A to F have been identified and characterised. Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the . Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for which can affect cardiac function and cause severe hypersensitivity) are not needed. Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.

An efficient total synthesis of (−)-epothilone B has been achieved in ca
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Previous article in issue: Total Synthesis of (−)-Epothilone A

The particular synthetic method determined by the laboratories of K.C Nicolaou, described the synthesis of appropriate building blocks 9, 11, and 12, derived from the retrosynthetic analysis of epothilone B (Figure 1), both diastereoisomers and the geometrical isomers at C6-C7 and C12-C13, can be obtained to give a diverse molecular product. The synthesis of required building blocks 9, 11 and 12, were obtained in a maximum of 4 steps for each building block as seen in Figure 2. With fragments 9, 11 and 12 in hand, these intermediates can then react with one another via , aldol reaction, macrolactonization, and epoxidation to give the various epothilone B as seen in Figure 3.

The formal total synthesis of epothilone A is described

Epothilone B is a 16-membered macrolactone with a methyl group connected to the macrocycle by an olefinic bond. The polyketide backbone was synthesized by type I (PKS) and the thiazole ring was derived from a incorporated by a (NRPS). In this biosythesis, both PKS and NRPS use , which have been post-translationally modified by phosphopantheteine groups, to join the growing chain. PKS uses thioester to catalyze the reaction and modify the substrates by selectively reducing the β carbonyl to the (Ketoreductase, KR), the (Dehydratase, DH), and the (Enoyl Reductase, ER). PKS-I can also the α carbon of the substrate. NRPS, on the other hand, uses activated on the enzyme as aminoacyl adenylates. Unlike PKS, , N-methylation, and heterocycle formation occurs in NRPS enzyme.

Total Synthesis Highlights - Organic Chemistry Portal

Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many . The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996. This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published by , Schinzer, Mulzer, and Carreira. In this approach, key building blocks , , and ketoacid were constructed and coupled to precursor via an and then an coupling. was employed to close the bis terminal olefin of the precursor compound. The resulting compounds were cis- and tran-macrocyclic isomers with distinct . of cis- and trans-olefins yield epothilone A and its analogues.

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