The Experts below are selected from a list of 117 Experts worldwide ranked by ideXlab platform
Paul W. Sylvester - One of the best experts on this subject based on the ideXlab platform.
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δ-Tocotrienol Oxazine Derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia.
BioMed research international, 2014Co-Authors: Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Alaadin Alayoubi, Sami Nazzal, Khalid A. El Sayed, Paul W. SylvesterAbstract:In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol Oxazine Derivative, compound 44, on
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δ-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia
Hindawi Limited, 2014Co-Authors: Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Alaadin Alayoubi, Sami Nazzal, Khalid El Sayed, Paul W. SylvesterAbstract:In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol Oxazine Derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol Oxazine Derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors
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Abstract P3-03-11: Oxazine Derivatives of g- and D- tocotrienols display potent anticancer effects in vivo
Poster Session Abstracts, 2013Co-Authors: Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Sami Nazzal, Aal Ayoubi, K.a. El Sayed, Paul W. SylvesterAbstract:Breast cancer is a multi-stage process which leads to the accumulation of abnormal cells arising from excessive proliferation, lack of apoptosis or a combination of both. Natural compounds such as g-tocotrienol have been shown to selectively inhibit cancer cell growth without harming normal cell viability with little or no adverse side effects. The antiproliferative and apoptotic effects of the tocotrienol isoform, γ-tocotrienol, have been firmly established in various cancer types. However, in vivo studies have provided mixed results, attributed to γ-tocotrienol rapid clearance and low bioavailability. In order to improve anticancer potency and bioavailability in vivo , γ- and Δ-tocotrienol were chemically modified with electrophilic substitution reactions on their chromane ring using Mannich and Lederer-Manasse reactions, resulting in the synthesis of various Oxazine Derivatives. Several of these Oxazine Derivatives (compounds 26, 31, 39, 40 and 44) were found to display potent anticancer activity as compared to their parent compounds when tested on +SA mammary cancer cells grown in culture. These in vitro studies were followed up with in vivo studies to determine the anticancer effects of Oxazine Derivatives on the growth of mammary tumors in mice. Female syngeneic BALB/c mice, 4-6 week old were inoculated with 1×10 6 +SA mammary tumor cells in the left mammary pad. Once tumor size reached 5mm in diameter, animals were divided into different treatment groups and received an intra-tumoral injection injected of 0-120μg/20μl tocotrienol or its Derivative every other day for 11 days. Afterwards, mice were sacrificed, tumors removed and placed in -80°C until further analysis. Results from these studies showed that tumor growth rate was significantly reduced in the Oxazine Derivative treated animals as compared to the vehicle-treated controls. Western blot analysis of tumor samples showed that the growth inhibitory effects of tocotrienol Derivatives was also associated with a significant reduction in phosphorylated (activated) Akt and reductions in cell cycle regulatory proteins cyclin D1 and cyclin dependent kinases (CDK2, CDK4 and CDK6). In addition, Oxazine Derivative treatment was also associated with a large increase in CDK inhibitors p21 and p27, as compared to tumors obtained from the vehicle-treated control mice. Western blot analysis also showed that tumor from Oxazine-Derivative treated mice displayed a large reduction in NFκB levels and its downstream gene product COX-2. In summary, Oxazine Derivatives of tocotrienols display more potent anticancer activity both in vitro and in vivo , as compared to their parent compounds and suggest that these tocotrienol Derivatives may provide some benefit as novel anticancer therapeutic agents. This work was supported, in part, by First Tec International Ltd. (Hong Kong), Malaysian Palm oil Council and the Louisiana Cancer Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-03-11.
Hans-ulrich Reissig - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Divalent Carbohydrate Mimetics by Reductive Amination with Enantiopure 1,2-Oxazines as Precursors
Synthesis, 2015Co-Authors: Joana Salta, Hans-ulrich ReissigAbstract:A direct approach to mono- and divalent carbohydrate mimetics starting from an enantiopure 1,2-Oxazine Derivative is described. After the Lewis acid induced rearrangement and subsequent reduction to provide the expected bicyclic 1,2-Oxazine Derivative as major component, a new tricyclic compound resulting from a different rearrangement pathway was isolated in small amounts. A smooth and optimized method for the hydrogenation of the bicyclic 1,2-Oxazine Derivative is presented, affording the desired aminopyran with d -idopyranose configuration. By reductive amination this aminopyran was connected with different aldehydes to furnish N-alkylated compounds. Reductive amination using 1,5-pentanedial resulted in the formation of a piperidine ring. With rigid aromatic dialdehydes the desired divalent compounds were obtained in good to excellent yields. Similar divalent carbohydrate mimetics were prepared from serinol.
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Synthesis of rigid p-terphenyl-linked carbohydrate mimetics
Beilstein-Institut, 2014Co-Authors: Maja Kandziora, Hans-ulrich ReissigAbstract:An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is described. Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki cross-couplings. The key compound, a p-bromophenyl-substituted 1,2-Oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE-allene. The Lewis acid-induced rearrangement of this heterocycle provided the corresponding bicyclic 1,2-Oxazine Derivative that may be regarded as internally protected amino sugar analogue. After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross-couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers
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Application of L‐Erythrose‐Derived Nitrones in the Synthesis of Polyhydroxylated Compounds via 3,6‐Dihydro‐2H‐1,2‐Oxazine Derivatives
European Journal of Organic Chemistry, 2012Co-Authors: Marcin Jasiński, Dieter Lentz, Elena Moreno-clavijo, Hans-ulrich ReissigAbstract:Enantiopure 3,6-dihydro-2H-1,2-Oxazines were prepared by [3+3] cyclisations starting from lithiated methoxyallene and the L-erythrose-derived nitrones 1′ and 3. The role of the side-chain protective group, which steers the highly selective formation of either anti- or syn-configured products, was demonstrated. A hydroboration/oxidation protocol smoothly converted 1,2-Oxazine Derivative syn-5 into secondary alcohol 6. After deprotection, polyhydroxylated tetrahydro-2H-1,2-Oxazine 11, which can be regarded as an azasugar, was isolated. Analogous treatment of 1,2-Oxazine anti-5 with the borane not only provided the expected secondary alcohol 7, but it also induced reduction of the C=C bond and ring opening. Treatment of syn-5 and anti-2 with hydrochloric acid in methanol induced deprotections and cyclisations leading to bicyclic tetrahydro-2H-1,2-Oxazine Derivatives. The second ring can be either a furan or a pyran ring. In the syn series, furan Derivative 12 was formed exclusively, and its hydrogenolysis led to enantiopure aminofuran Derivative 14. Acid-promoted rearrangement of unprotected anti-2 led to a mixture of bicyclic compounds with furan or pyran rings fused to the 1,2-Oxazine core. However, when TBDPS-protected compound 20 was used it cleanly led to 1,2-Oxazine 21 with a fused furan ring and then to aminofuran 22. Alternatively, the N–O bond in unprotected anti-2 was chemoselectively reduced with samarium diiodide, efficiently generating highly functionalized allylic alcohol 23. Acid-promoted cyclisation and deprotection furnished furan Derivative 24. Mechanistic suggestions to explain the different outcomes of the acid-induced transformations are provided. Overall, it is demonstrated that the stereodivergent addition of lithiated alkoxyallenes to L-erythrose-derived nitrones allow flexible access to a series of enantiopure amino polyols, including aminofuran Derivatives.
Herbert A. Kirst - One of the best experts on this subject based on the ideXlab platform.
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synthesis and antimicrobial evaluation of dirithromycin as e 136 ly237216 a new macrolide antibiotic derived from erythromycin
Antimicrobial Agents and Chemotherapy, 1991Co-Authors: F T Counter, P W Ensminger, C Y E Wu, J M Greene, A M Feltyduckworth, D. A. Preston, Jonathan W. Paschal, Herbert A. KirstAbstract:Dirithromycin is a 9-N-11-O-Oxazine Derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.
Suryatheja Ananthula - One of the best experts on this subject based on the ideXlab platform.
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δ-Tocotrienol Oxazine Derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia.
BioMed research international, 2014Co-Authors: Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Alaadin Alayoubi, Sami Nazzal, Khalid A. El Sayed, Paul W. SylvesterAbstract:In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol Oxazine Derivative, compound 44, on
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δ-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia
Hindawi Limited, 2014Co-Authors: Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Alaadin Alayoubi, Sami Nazzal, Khalid El Sayed, Paul W. SylvesterAbstract:In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol Oxazine Derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol Oxazine Derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors
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Abstract P3-03-11: Oxazine Derivatives of g- and D- tocotrienols display potent anticancer effects in vivo
Poster Session Abstracts, 2013Co-Authors: Suryatheja Ananthula, Parash Parajuli, Fathy A. Behery, Sami Nazzal, Aal Ayoubi, K.a. El Sayed, Paul W. SylvesterAbstract:Breast cancer is a multi-stage process which leads to the accumulation of abnormal cells arising from excessive proliferation, lack of apoptosis or a combination of both. Natural compounds such as g-tocotrienol have been shown to selectively inhibit cancer cell growth without harming normal cell viability with little or no adverse side effects. The antiproliferative and apoptotic effects of the tocotrienol isoform, γ-tocotrienol, have been firmly established in various cancer types. However, in vivo studies have provided mixed results, attributed to γ-tocotrienol rapid clearance and low bioavailability. In order to improve anticancer potency and bioavailability in vivo , γ- and Δ-tocotrienol were chemically modified with electrophilic substitution reactions on their chromane ring using Mannich and Lederer-Manasse reactions, resulting in the synthesis of various Oxazine Derivatives. Several of these Oxazine Derivatives (compounds 26, 31, 39, 40 and 44) were found to display potent anticancer activity as compared to their parent compounds when tested on +SA mammary cancer cells grown in culture. These in vitro studies were followed up with in vivo studies to determine the anticancer effects of Oxazine Derivatives on the growth of mammary tumors in mice. Female syngeneic BALB/c mice, 4-6 week old were inoculated with 1×10 6 +SA mammary tumor cells in the left mammary pad. Once tumor size reached 5mm in diameter, animals were divided into different treatment groups and received an intra-tumoral injection injected of 0-120μg/20μl tocotrienol or its Derivative every other day for 11 days. Afterwards, mice were sacrificed, tumors removed and placed in -80°C until further analysis. Results from these studies showed that tumor growth rate was significantly reduced in the Oxazine Derivative treated animals as compared to the vehicle-treated controls. Western blot analysis of tumor samples showed that the growth inhibitory effects of tocotrienol Derivatives was also associated with a significant reduction in phosphorylated (activated) Akt and reductions in cell cycle regulatory proteins cyclin D1 and cyclin dependent kinases (CDK2, CDK4 and CDK6). In addition, Oxazine Derivative treatment was also associated with a large increase in CDK inhibitors p21 and p27, as compared to tumors obtained from the vehicle-treated control mice. Western blot analysis also showed that tumor from Oxazine-Derivative treated mice displayed a large reduction in NFκB levels and its downstream gene product COX-2. In summary, Oxazine Derivatives of tocotrienols display more potent anticancer activity both in vitro and in vivo , as compared to their parent compounds and suggest that these tocotrienol Derivatives may provide some benefit as novel anticancer therapeutic agents. This work was supported, in part, by First Tec International Ltd. (Hong Kong), Malaysian Palm oil Council and the Louisiana Cancer Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-03-11.
Sakae Aoyagi - One of the best experts on this subject based on the ideXlab platform.
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Total synthesis of (-)-chamobtusin A.
Organic letters, 2012Co-Authors: Hikaru Suzuki, Sakae AoyagiAbstract:The first asymmetric total synthesis of a structurally unique alkaloid, chamobtusin A (1), is described. The route features a novel aziridine formation from the 1,2-Oxazine Derivative and a palladium-mediated annulation of the vinylaziridine intermediate.
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Total Synthesis of (−)-Chamobtusin A
2012Co-Authors: Hikaru Suzuki, Sakae AoyagiAbstract:The first asymmetric total synthesis of a structurally unique alkaloid, chamobtusin A (1), is described. The route features a novel aziridine formation from the 1,2-Oxazine Derivative and a palladium-mediated annulation of the vinylaziridine intermediate
