The Experts below are selected from a list of 30 Experts worldwide ranked by ideXlab platform
Rita Bernhardt - One of the best experts on this subject based on the ideXlab platform.
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highly efficient cyp167a1 epok dependent Epothilone b formation and production of 7 ketone Epothilone d as a new Epothilone Derivative
Scientific Reports, 2015Co-Authors: Fredy Kern, Tobias Dier, Yogan Khatri, Kerstin Maria Ewen, Jeanpierre Jacquot, Dietrich A Volmer, Rita BernhardtAbstract:Since their discovery in the soil bacterium Sorangium cellulosum, Epothilones have emerged as a valuable substance class with promising anti-tumor activity. Because of their benefits in the treatment of cancer and neurodegenerative diseases, Epothilones are targets for drug design and pharmaceutical research. The final step of their biosynthesis – a cytochrome P450 mediated epoxidation of Epothilone C/D to A/B by CYP167A1 (EpoK) – needs significant improvement, in particular regarding the efficiency of its redox partners. Therefore, we have investigated the ability of various hetero- and homologous redox partners to transfer electrons to EpoK. Hereby, a new hybrid system was established with conversion rates eleven times higher and Vmax of more than seven orders of magnitudes higher as compared with the previously described spinach redox chain. This hybrid system is the most efficient redox chain for EpoK described to date. Furthermore, P450s from So ce56 were identified which are able to convert Epothilone D to 14-OH, 21-OH, 26-OH Epothilone D and 7-ketone Epothilone D. The latter one represents a novel Epothilone Derivative and is a suitable candidate for pharmacological tests. The results revealed myxobacterial P450s from S. cellulosum So ce56 as promising candidates for protein engineering for biotechnological production of Epothilone Derivatives.
Johann Mulzer - One of the best experts on this subject based on the ideXlab platform.
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the 12 13 diol cyclization approach for a truly stereocontrolled total synthesis of Epothilone b and the synthesis of a conformationally restrained analogue
Chemistry: A European Journal, 2001Co-Authors: Harry J Martin, Peter Pojarliev, Hanspeter Kahlig, Johann MulzerAbstract:: A highly convergent and stereocontrolled synthesis of Epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol addition of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-beta-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone Derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained Epothilone Derivative 42.
Fredy Kern - One of the best experts on this subject based on the ideXlab platform.
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highly efficient cyp167a1 epok dependent Epothilone b formation and production of 7 ketone Epothilone d as a new Epothilone Derivative
Scientific Reports, 2015Co-Authors: Fredy Kern, Tobias Dier, Yogan Khatri, Kerstin Maria Ewen, Jeanpierre Jacquot, Dietrich A Volmer, Rita BernhardtAbstract:Since their discovery in the soil bacterium Sorangium cellulosum, Epothilones have emerged as a valuable substance class with promising anti-tumor activity. Because of their benefits in the treatment of cancer and neurodegenerative diseases, Epothilones are targets for drug design and pharmaceutical research. The final step of their biosynthesis – a cytochrome P450 mediated epoxidation of Epothilone C/D to A/B by CYP167A1 (EpoK) – needs significant improvement, in particular regarding the efficiency of its redox partners. Therefore, we have investigated the ability of various hetero- and homologous redox partners to transfer electrons to EpoK. Hereby, a new hybrid system was established with conversion rates eleven times higher and Vmax of more than seven orders of magnitudes higher as compared with the previously described spinach redox chain. This hybrid system is the most efficient redox chain for EpoK described to date. Furthermore, P450s from So ce56 were identified which are able to convert Epothilone D to 14-OH, 21-OH, 26-OH Epothilone D and 7-ketone Epothilone D. The latter one represents a novel Epothilone Derivative and is a suitable candidate for pharmacological tests. The results revealed myxobacterial P450s from S. cellulosum So ce56 as promising candidates for protein engineering for biotechnological production of Epothilone Derivatives.
Richard Smykla - One of the best experts on this subject based on the ideXlab platform.
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in vivo evaluation of ixabepilone bms247550 a novel Epothilone b Derivative against pediatric cancer models
Clinical Cancer Research, 2005Co-Authors: Jennifer K Peterson, Chandra Tucker, Edward Favours, Pamela J Cheshire, Jeremy Creech, Catherine A Billups, Richard SmyklaAbstract:Purpose: Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types. The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an Epothilone B Derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models. Experimental Design: Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four), Wilms9 tumors (six), osteosarcoma (four), or brain tumors (seven). Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg). Results: At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved ≥50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms9 tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (≥50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone. Pharmacokinetics following single i.v. administration of ixabepilone at its MTD (10 mg/kg) were biexponential with C max of 12.5 μmol/L, elimination half-life of 19.2 hours, and total area under the curve of 5.8 μmol/L-h. The achieved drug exposure of ixabepilone at this efficacious MTD dose level in mice is similar to those achieved in patients given the recommended phase II dose of 40 mg/m 2 by either 1- or 3-hour infusion every 3 weeks, a regimen that has shown significant anticancer activity in phase II clinical trials in adult patients. Conclusions: Administered at doses ranging from 66% to 100% of its MTD in mice, the Epothilone B Derivative ixabepilone shows broad spectrum activity against a panel of pediatric tumor xenograft models. Pharmacokinetic analysis indicates that the systemic ixabepilone exposure achieved in mice at its MTD is similar to that achieved in patients at the recommended phase II dose of 40 mg/m 2 administered every 3 weeks. Importantly, the present results showed a clear distinction in sensitivity of pediatric solid tumors to this Epothilone Derivative compared with paclitaxel.
Harry J Martin - One of the best experts on this subject based on the ideXlab platform.
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the 12 13 diol cyclization approach for a truly stereocontrolled total synthesis of Epothilone b and the synthesis of a conformationally restrained analogue
Chemistry: A European Journal, 2001Co-Authors: Harry J Martin, Peter Pojarliev, Hanspeter Kahlig, Johann MulzerAbstract:: A highly convergent and stereocontrolled synthesis of Epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol addition of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-beta-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone Derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained Epothilone Derivative 42.