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Renzo Rossi - One of the best experts on this subject based on the ideXlab platform.
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An Economical Access to 3,4‐Diaryl‐2(5H)‐furanones and 4‐Aryl‐6‐methyl‐2(2H)‐pyranones by Pd‐Catalyzed Suzuki‐Type Arylation of 3‐Aryl‐4‐tosyloxy‐2(5H)‐furanones and 6‐Methyl‐4‐tosyloxy‐2(2H)‐pyranones, Respectively
European Journal of Organic Chemistry, 2009Co-Authors: Fabio Bellina, Chiara Marchetti, Renzo RossiAbstract:Both symmetrical and unsymmetrical 3,4-diaryl-substituted 2(5H)-furanones have been efficiently synthesized using an inexpensive procedure involving the Pd(OAc)2/PCy3-catalyzed Suzuki-type arylation of readily available 3-aryl-4-tosyloxy-2(5H)-furanones as the key step. The mild conditions of this arylation protocol have also been used for the high yielding synthesis of 4-aryl-6-methyl-2(2H)-pyranones from 6-methyl-4-tosyloxy-2(2H)-pyranone. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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6-Chloro-2(2H)-pyranone: a new 2(2H)-pyranone synthon
Tetrahedron Letters, 2003Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Renzo RossiAbstract:6-Chloro-2(2H)-pyranone, which can be prepared in high yield from commercially available trans-glutaconic acid, undergoes facile Pd/Cu-catalyzed reaction with various 1-alkynes to give rise to the corresponding 6-(1-alkynyl)-2(2H)-pyranones in moderate to good yields. These last hitherto unknown compounds have been used as direct precursors to 6-alkyl- and 6-[(Z)-1-alkenyl]-2(2H)-pyranones.
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New procedures for the selective synthesis of 2(2H)-pyranone derivatives and 3-aryl-4-iodoisocoumarins
Tetrahedron, 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Paolo Stabile, Fabio Bellina, Renzo RossiAbstract:Abstract 5-Iodo-2(2 H )-pyranone derivatives have been selectively synthesized by reaction of stereodefined methyl 2-en-4-ynoates with iodine in MeCN, CH 2 Cl 2 or C 6 H 6 at 20°C (Method C) or by treatment of these esters with ICl in CH 2 Cl 2 at 20°C (Method B). Methods B and C proved also to be suitable for the preparation of 3-aryl-4-iodoisocoumarins from the corresponding methyl 2-(arylethynyl)benzoates. Interestingly, the high selectivity of iodolactonization of stereodefined methyl 2-en-4-ynoates by Method B allowed preparation in moderate yields of 2(2 H )-pyranone derivatives by a one-pot sequence of iodolactonization and Stille-type reactions.
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Selective Synthesis of 5,6‐Disubstituted 3‐Methyl‐2(2H)‐pyranones and 6‐Substituted 3‐Methyl‐2(2H)‐pyranones, Including Fusalanipyrone and Gibepyrone A
European Journal of Organic Chemistry, 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Stéphane Viel, Luisa Mannina, Renzo RossiAbstract:The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones 11, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones 8 and 6-substituted 3-methyl-2(2H)-pyranones 7. The synthesis of compounds 8 involved two consecutive Stille-type reactions, whereas the approach followed to prepare compounds 7 consisted of the selective reduction of the dihalogen derivatives 11 to the corresponding 6-substituted 3-bromo-2(2H)-pyranones 12, followed by a Pd/Cu-catalysed reaction with tetramethyltin. However, this synthetic approach to compounds 7 proved to be unsuitable for preparing stereoisomerically pure fusalanipyrone (7a), a natural product isolated from Fusarium solani. Nevertheless, 7a and gibepyrone A (7b), which is a natural product isolated from Gibberella fujikuroi, could be synthesized in stereoisomerically pure form by reaction sequences involving iodolactonization of easily available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4-ynoic acids (16a) and (16b), respectively, followed by Pd-catalysed triethylammonium formate reduction of the thus obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranones 17a and 17b, respectively. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
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Selective synthesis of 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones, including fusalanipyrone and gibepyrone A
'Wiley', 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Stéphane Viel, Luisa Mannina, Renzo RossiAbstract:The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones . The synthesis of compounds involved two consecutive Stille-type reactions, whereas the approach followed to prepare compounds consisted of the selective reduction of the dihalogen derivatives to the corresponding 6-substituted 3-bromo-2(2H)-pyranones , followed by a Pd/Cu-catalysed reaction with tetramethyltin. However, this synthetic approach to compounds proved to be unsuitable for preparing stereoisomerically pure fusalanipyrone, a natural product isolated from Fusarium solani. Nevertheless, this compound which is a natural product isolated from Gibberella fujikuroi, could be synthesized in stereoisomerically pure form by reaction sequences involving iodolactonization of easily available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4- ynoic acids, followed by Pd catalysed triethylammonium formate reduction of the thus obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranone
Fabio Bellina - One of the best experts on this subject based on the ideXlab platform.
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An Economical Access to 3,4‐Diaryl‐2(5H)‐furanones and 4‐Aryl‐6‐methyl‐2(2H)‐pyranones by Pd‐Catalyzed Suzuki‐Type Arylation of 3‐Aryl‐4‐tosyloxy‐2(5H)‐furanones and 6‐Methyl‐4‐tosyloxy‐2(2H)‐pyranones, Respectively
European Journal of Organic Chemistry, 2009Co-Authors: Fabio Bellina, Chiara Marchetti, Renzo RossiAbstract:Both symmetrical and unsymmetrical 3,4-diaryl-substituted 2(5H)-furanones have been efficiently synthesized using an inexpensive procedure involving the Pd(OAc)2/PCy3-catalyzed Suzuki-type arylation of readily available 3-aryl-4-tosyloxy-2(5H)-furanones as the key step. The mild conditions of this arylation protocol have also been used for the high yielding synthesis of 4-aryl-6-methyl-2(2H)-pyranones from 6-methyl-4-tosyloxy-2(2H)-pyranone. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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6-Chloro-2(2H)-pyranone: a new 2(2H)-pyranone synthon
Tetrahedron Letters, 2003Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Renzo RossiAbstract:6-Chloro-2(2H)-pyranone, which can be prepared in high yield from commercially available trans-glutaconic acid, undergoes facile Pd/Cu-catalyzed reaction with various 1-alkynes to give rise to the corresponding 6-(1-alkynyl)-2(2H)-pyranones in moderate to good yields. These last hitherto unknown compounds have been used as direct precursors to 6-alkyl- and 6-[(Z)-1-alkenyl]-2(2H)-pyranones.
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New procedures for the selective synthesis of 2(2H)-pyranone derivatives and 3-aryl-4-iodoisocoumarins
Tetrahedron, 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Paolo Stabile, Fabio Bellina, Renzo RossiAbstract:Abstract 5-Iodo-2(2 H )-pyranone derivatives have been selectively synthesized by reaction of stereodefined methyl 2-en-4-ynoates with iodine in MeCN, CH 2 Cl 2 or C 6 H 6 at 20°C (Method C) or by treatment of these esters with ICl in CH 2 Cl 2 at 20°C (Method B). Methods B and C proved also to be suitable for the preparation of 3-aryl-4-iodoisocoumarins from the corresponding methyl 2-(arylethynyl)benzoates. Interestingly, the high selectivity of iodolactonization of stereodefined methyl 2-en-4-ynoates by Method B allowed preparation in moderate yields of 2(2 H )-pyranone derivatives by a one-pot sequence of iodolactonization and Stille-type reactions.
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Selective Synthesis of 5,6‐Disubstituted 3‐Methyl‐2(2H)‐pyranones and 6‐Substituted 3‐Methyl‐2(2H)‐pyranones, Including Fusalanipyrone and Gibepyrone A
European Journal of Organic Chemistry, 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Stéphane Viel, Luisa Mannina, Renzo RossiAbstract:The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones 11, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones 8 and 6-substituted 3-methyl-2(2H)-pyranones 7. The synthesis of compounds 8 involved two consecutive Stille-type reactions, whereas the approach followed to prepare compounds 7 consisted of the selective reduction of the dihalogen derivatives 11 to the corresponding 6-substituted 3-bromo-2(2H)-pyranones 12, followed by a Pd/Cu-catalysed reaction with tetramethyltin. However, this synthetic approach to compounds 7 proved to be unsuitable for preparing stereoisomerically pure fusalanipyrone (7a), a natural product isolated from Fusarium solani. Nevertheless, 7a and gibepyrone A (7b), which is a natural product isolated from Gibberella fujikuroi, could be synthesized in stereoisomerically pure form by reaction sequences involving iodolactonization of easily available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4-ynoic acids (16a) and (16b), respectively, followed by Pd-catalysed triethylammonium formate reduction of the thus obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranones 17a and 17b, respectively. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
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Selective synthesis of 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones, including fusalanipyrone and gibepyrone A
'Wiley', 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Stéphane Viel, Luisa Mannina, Renzo RossiAbstract:The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones . The synthesis of compounds involved two consecutive Stille-type reactions, whereas the approach followed to prepare compounds consisted of the selective reduction of the dihalogen derivatives to the corresponding 6-substituted 3-bromo-2(2H)-pyranones , followed by a Pd/Cu-catalysed reaction with tetramethyltin. However, this synthetic approach to compounds proved to be unsuitable for preparing stereoisomerically pure fusalanipyrone, a natural product isolated from Fusarium solani. Nevertheless, this compound which is a natural product isolated from Gibberella fujikuroi, could be synthesized in stereoisomerically pure form by reaction sequences involving iodolactonization of easily available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4- ynoic acids, followed by Pd catalysed triethylammonium formate reduction of the thus obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranone
Atul Goel - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Solution-Processable Donor-Acceptor Pyranone Dyads for White Organic Light-Emitting Devices.
The Journal of organic chemistry, 2019Co-Authors: Chandra P. Sharma, Neeraj M. Gupta, Jagriti Singh, Rohit Ashok Kumar Yadav, Deepak Kumar Dubey, Kundan S. Rawat, Ajay K. Jha, Jwo-huei Jou, Atul GoelAbstract:A series of donor–acceptor pyranones (3a–m, 4a–h) were synthesized using α-oxo-ketene-S,S-acetal as the synthon for their application as emissive materials for energy-saving organic light-emitting devices (OLEDs). Among them, five pyranones 3f, 3g, 3h, 3m, and 4e exhibited highly bright fluorescence in the solid state and weak or no emission in the solution state. Photophysical analysis of these dyes revealed that only 3f and 3m showed aggregation-induced emission behavior in a THF/water mixture (0–99%) with varying water fractions (fw) leading to bright fluorescence covering the entire visible region, while other derivatives 3g, 3h, and 4e did not show any fluorescence signal. The computational studies of the compounds revealed that the longer wavelength absorption originates from HOMO to LUMO electronic excitation. These dyes exhibited good thermal stability with 5% weight loss temperature in the range of 218–347 °C. The potential application of the donor–acceptor pyranone dyads was demonstrated by fabr...
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synthesis of solution processable donor acceptor pyranone dyads for white organic light emitting devices
Journal of Organic Chemistry, 2019Co-Authors: Chandra P. Sharma, Neeraj M. Gupta, Jagriti Singh, Rohit Ashok Kumar Yadav, Deepak Kumar Dubey, Kundan S. Rawat, Ajay K. Jha, Jwo-huei Jou, Atul GoelAbstract:A series of donor-acceptor pyranones (3a-m, 4a-h) were synthesized using α-oxo-ketene- S, S-acetal as the synthon for their application as emissive materials for energy-saving organic light-emitting devices (OLEDs). Among them, five pyranones 3f, 3g, 3h, 3m, and 4e exhibited highly bright fluorescence in the solid state and weak or no emission in the solution state. Photophysical analysis of these dyes revealed that only 3f and 3m showed aggregation-induced emission behavior in a THF/water mixture (0-99%) with varying water fractions ( fw) leading to bright fluorescence covering the entire visible region, while other derivatives 3g, 3h, and 4e did not show any fluorescence signal. The computational studies of the compounds revealed that the longer wavelength absorption originates from HOMO to LUMO electronic excitation. These dyes exhibited good thermal stability with 5% weight loss temperature in the range of 218-347 °C. The potential application of the donor-acceptor pyranone dyads was demonstrated by fabrication of solution-processed OLEDs. Remarkably, OLED devices prepared using highly emissive compounds 6-(anthracen-9-yl)-4-(methylthio)-2-oxo-2 H-pyran-3-carbonitrile (3m) and 6-(4-methoxyphenyl)-4-(methylthio)-2-oxo-2 H-pyran-3-carbonitrile (3f) displayed pure white emission with CIE coordinates of (0.29, 0.31) and (0.32, 0.32), respectively. Additionally, the resultant devices exhibited external quantum efficiencies of 1.9 and 1.2% at 100 cd m-2, respectively.
Matteo Biagetti - One of the best experts on this subject based on the ideXlab platform.
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6-Chloro-2(2H)-pyranone: a new 2(2H)-pyranone synthon
Tetrahedron Letters, 2003Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Renzo RossiAbstract:6-Chloro-2(2H)-pyranone, which can be prepared in high yield from commercially available trans-glutaconic acid, undergoes facile Pd/Cu-catalyzed reaction with various 1-alkynes to give rise to the corresponding 6-(1-alkynyl)-2(2H)-pyranones in moderate to good yields. These last hitherto unknown compounds have been used as direct precursors to 6-alkyl- and 6-[(Z)-1-alkenyl]-2(2H)-pyranones.
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New procedures for the selective synthesis of 2(2H)-pyranone derivatives and 3-aryl-4-iodoisocoumarins
Tetrahedron, 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Paolo Stabile, Fabio Bellina, Renzo RossiAbstract:Abstract 5-Iodo-2(2 H )-pyranone derivatives have been selectively synthesized by reaction of stereodefined methyl 2-en-4-ynoates with iodine in MeCN, CH 2 Cl 2 or C 6 H 6 at 20°C (Method C) or by treatment of these esters with ICl in CH 2 Cl 2 at 20°C (Method B). Methods B and C proved also to be suitable for the preparation of 3-aryl-4-iodoisocoumarins from the corresponding methyl 2-(arylethynyl)benzoates. Interestingly, the high selectivity of iodolactonization of stereodefined methyl 2-en-4-ynoates by Method B allowed preparation in moderate yields of 2(2 H )-pyranone derivatives by a one-pot sequence of iodolactonization and Stille-type reactions.
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Selective Synthesis of 5,6‐Disubstituted 3‐Methyl‐2(2H)‐pyranones and 6‐Substituted 3‐Methyl‐2(2H)‐pyranones, Including Fusalanipyrone and Gibepyrone A
European Journal of Organic Chemistry, 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Stéphane Viel, Luisa Mannina, Renzo RossiAbstract:The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones 11, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones 8 and 6-substituted 3-methyl-2(2H)-pyranones 7. The synthesis of compounds 8 involved two consecutive Stille-type reactions, whereas the approach followed to prepare compounds 7 consisted of the selective reduction of the dihalogen derivatives 11 to the corresponding 6-substituted 3-bromo-2(2H)-pyranones 12, followed by a Pd/Cu-catalysed reaction with tetramethyltin. However, this synthetic approach to compounds 7 proved to be unsuitable for preparing stereoisomerically pure fusalanipyrone (7a), a natural product isolated from Fusarium solani. Nevertheless, 7a and gibepyrone A (7b), which is a natural product isolated from Gibberella fujikuroi, could be synthesized in stereoisomerically pure form by reaction sequences involving iodolactonization of easily available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4-ynoic acids (16a) and (16b), respectively, followed by Pd-catalysed triethylammonium formate reduction of the thus obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranones 17a and 17b, respectively. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
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Selective synthesis of 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones, including fusalanipyrone and gibepyrone A
'Wiley', 2002Co-Authors: Matteo Biagetti, Adriano Carpita, Fabio Bellina, Stéphane Viel, Luisa Mannina, Renzo RossiAbstract:The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones . The synthesis of compounds involved two consecutive Stille-type reactions, whereas the approach followed to prepare compounds consisted of the selective reduction of the dihalogen derivatives to the corresponding 6-substituted 3-bromo-2(2H)-pyranones , followed by a Pd/Cu-catalysed reaction with tetramethyltin. However, this synthetic approach to compounds proved to be unsuitable for preparing stereoisomerically pure fusalanipyrone, a natural product isolated from Fusarium solani. Nevertheless, this compound which is a natural product isolated from Gibberella fujikuroi, could be synthesized in stereoisomerically pure form by reaction sequences involving iodolactonization of easily available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4- ynoic acids, followed by Pd catalysed triethylammonium formate reduction of the thus obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranone
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selective synthesis of natural and unnatural 5 6 disubstituted 2 2h pyranones via iodolactonization of 5 substituted z 2 en 4 ynoic acids
Tetrahedron, 2001Co-Authors: Fabio Bellina, Adriano Carpita, Matteo Biagetti, Renzo RossiAbstract:Abstract Reaction of 5-substituted ( Z )-2-en-4-ynoic acids with iodine and NaHCO 3 in CH 3 CN or with ICl in CH 2 Cl 2 affords mixtures of ( E )-5-(1-iodoylidene)-2(5 H )-furanones and 6-substituted 5-iodo-2(2 H )-pyranones in which these last compounds are the major products. The 5-iodo-2(2 H )-pyranones, which are easily separated chromatographically from the corresponding regioisomers, are able to undergo Stille-type reactions with a variety of organotin compounds to give 5,6-disubstituted 2(2 H )-pyranones in moderate to good yields. One of these compounds, i.e. 5-(1-butynyl)-2(2 H )-pyranone, has been used as direct precursor to two substances produced by fungal culture LL-11G219, which function as androgen ligands, i.e. ( Z )-5-(1-butenyl)-6-methyl-2(2 H )-pyranone and 5-butyl-6-methyl-2(2 H )-pyranone.
Shailja Singh - One of the best experts on this subject based on the ideXlab platform.
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Correction to: Enhanced uptake, high selective and microtubule disrupting activity of carbohydrate fused pyrano-pyranones derived from natural coumarins attributes to its anti-malarial potential.
Malaria journal, 2020Co-Authors: Sonal Gupta, Priti Kumari, Chintam Narayana, Ram Sagar, Juveria Khan, R Ayana, Malabika Chakrabarti, Shailja SinghAbstract:Malaria is one of the deadliest infectious diseases caused by protozoan parasite of Plasmodium spp. Increasing resistance to anti-malarials has become global threat in control of the disease and demands for novel anti-malarial interventions. Naturally-occurring coumarins, which belong to a class of benzo-α-pyrones, found in higher plants and some essential oils, exhibit therapeutic potential against various diseases. However, their limited uptake and non-specificity has restricted their wide spread use as potential drug candidates. Two series of carbohydrate fused pyrano[3,2-c]pyranone carbohybrids which were synthesized by combination of 2-C-formyl galactal and 2-C-formyl glucal, with various freshly prepared 4-hydroxycoumarins were screened against Plasmodium falciparum. The anti-malarial activity of these carbohybrids was determined by growth inhibition assay on P. falciparum 3D7 strain using SYBR green based fluorescence assay. Haemolytic activity of carbohybrid 12, which showed maximal anti-malarial activity, was determined by haemocompatibility assay. The uptake of the carbohybrid 12 by parasitized erythrocytes was determined using confocal microscopy. Growth progression assays were performed to determine the stage specific effect of carbohybrid 12 treatment on Pf3D7. In silico studies were conducted to explore the mechanism of action of carbohybrid 12 on parasite microtubule dynamics. These findings were further validated by immunofluorescence assay and drug combination assay. 2-C-formyl galactal fused pyrano[3,2-c]pyranone carbohybrid 12 exhibited maximum growth inhibitory potential against Plasmodium with IC50 value of 5.861 µM and no toxicity on HepG2 cells as well as no haemolysis of erythrocytes. An enhanced uptake of this carbohybrid compound was observed by parasitized erythrocytes as compared to uninfected erythrocytes. Further study revealed that carbohybrid 12 arrests the growth of parasite at trophozoite and schizonts stage during course of progression through asexual blood stages. Mechanistically, it was shown that the carbohybrid 12 binds to α,β-heterodimer of tubulin and affects microtubule dynamics. These findings show carbohydrate group fusion to 4-hydroxycoumarin precursor resulted in pyrano-pyranones derivatives with better solubility, enhanced uptake and improved selectivity. This data confirms that, carbohydrate fused pyrano[3,2-c]pyranones carbohybrids are effective candidates for anti-malarial interventions against P. falciparum.
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Enhanced uptake, high selective and microtubule disrupting activity of carbohydrate fused pyrano-pyranones derived from natural coumarins attributes to its anti-malarial potential.
Malaria journal, 2019Co-Authors: Sonal Gupta, Priti Kumari, Chintam Narayana, Ram Sagar, Juveria Khan, R Ayana, Malabika Chakrabarti, Shailja SinghAbstract:Malaria is one of the deadliest infectious diseases caused by protozoan parasite of Plasmodium spp. Increasing resistance to anti-malarials has become global threat in control of the disease and demands for novel anti-malarial interventions. Naturally-occurring coumarins, which belong to a class of benzo-α-pyrones, found in higher plants and some essential oils, exhibit therapeutic potential against various diseases. However, their limited uptake and non-specificity has restricted their wide spread use as potential drug candidates. Two series of carbohydrate fused pyrano[3,2-c]pyranone carbohybrids which were synthesized by combination of 2-C-formyl galactal and 2-C-formyl glucal, with various freshly prepared 4-hydroxycoumarins were screened against Plasmodium falciparum. The anti-malarial activity of these carbohybrids was determined by growth inhibition assay on P. falciparum 3D7 strain using SYBR green based fluorescence assay. Haemolytic activity of carbohybrid 12, which showed maximal anti-malarial activity, was determined by haemocompatibility assay. The uptake of the carbohybrid 12 by parasitized erythrocytes was determined using confocal microscopy. Growth progression assays were performed to determine the stage specific effect of carbohybrid 12 treatment on Pf3D7. In silico studies were conducted to explore the mechanism of action of carbohybrid 12 on parasite microtubule dynamics. These findings were further validated by immunofluorescence assay and drug combination assay. 2-C-formyl galactal fused pyrano[3,2-c]pyranone carbohybrid 12 exhibited maximum growth inhibitory potential against Plasmodium with IC50 value of 5.861 µM and no toxicity on HepG2 cells as well as no haemolysis of erythrocytes. An enhanced uptake of this carbohybrid compound was observed by parasitized erythrocytes as compared to uninfected erythrocytes. Further study revealed that carbohybrid 12 arrests the growth of parasite at trophozoite and schizonts stage during course of progression through asexual blood stages. Mechanistically, it was shown that the carbohybrid 12 binds to α,β-heterodimer of tubulin and affects microtubule dynamics. These findings show carbohydrate group fusion to 4-hydroxycoumarin precursor resulted in pyrano-pyranones derivatives with better solubility, enhanced uptake and improved selectivity. This data confirms that, carbohydrate fused pyrano[3,2-c]pyranones carbohybrids are effective candidates for anti-malarial interventions against P. falciparum.
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Enhanced uptake, high selective and microtubule disrupting activity of carbohydrate fused pyrano-pyranones derived from natural coumarins attributes to its anti-malarial potential
Malaria Journal, 2019Co-Authors: Sonal Gupta, Priti Kumari, Chintam Narayana, Ram Sagar, Juveria Khan, R Ayana, Malabika Chakrabarti, Shailja SinghAbstract:Background Malaria is one of the deadliest infectious diseases caused by protozoan parasite of Plasmodium spp. Increasing resistance to anti-malarials has become global threat in control of the disease and demands for novel anti-malarial interventions. Naturally-occurring coumarins, which belong to a class of benzo-α-pyrones, found in higher plants and some essential oils, exhibit therapeutic potential against various diseases. However, their limited uptake and non-specificity has restricted their wide spread use as potential drug candidates. Methods Two series of carbohydrate fused pyrano[3,2-c]pyranone carbohybrids which were synthesized by combination of 2- C -formyl galactal and 2- C -formyl glucal, with various freshly prepared 4-hydroxycoumarins were screened against Plasmodium falciparum . The anti-malarial activity of these carbohybrids was determined by growth inhibition assay on P. falciparum 3D7 strain using SYBR green based fluorescence assay. Haemolytic activity of carbohybrid 12 , which showed maximal anti-malarial activity, was determined by haemocompatibility assay. The uptake of the carbohybrid 12 by parasitized erythrocytes was determined using confocal microscopy. Growth progression assays were performed to determine the stage specific effect of carbohybrid 12 treatment on Pf3D7. In silico studies were conducted to explore the mechanism of action of carbohybrid 12 on parasite microtubule dynamics. These findings were further validated by immunofluorescence assay and drug combination assay. Results 2-C-formyl galactal fused pyrano[3,2-c]pyranone carbohybrid 12 exhibited maximum growth inhibitory potential against Plasmodium with IC_50 value of 5.861 µM and no toxicity on HepG2 cells as well as no haemolysis of erythrocytes. An enhanced uptake of this carbohybrid compound was observed by parasitized erythrocytes as compared to uninfected erythrocytes. Further study revealed that carbohybrid 12 arrests the growth of parasite at trophozoite and schizonts stage during course of progression through asexual blood stages. Mechanistically, it was shown that the carbohybrid 12 binds to α,β-heterodimer of tubulin and affects microtubule dynamics. Conclusion These findings show carbohydrate group fusion to 4-hydroxycoumarin precursor resulted in pyrano-pyranones derivatives with better solubility, enhanced uptake and improved selectivity. This data confirms that, carbohydrate fused pyrano[3,2-c]pyranones carbohybrids are effective candidates for anti-malarial interventions against P. falciparum .
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Stereoselective synthesis of carbohydrate fused pyrano[3,2-c]pyranones as anticancer agents
New Journal of Chemistry, 2018Co-Authors: Priti Kumari, Sonal Gupta, Chintam Narayana, Shakeel Ahmad, Nidhi Vishnoi, Shailja Singh, Ram SagarAbstract:Pyrano[3,2-c]pyranone is an important structural motif present in many natural products exhibiting diverse biological activities. Two series of carbohydrate fused pyrano[3,2-c]pyranone derivatives (n = 20) were efficiently synthesized starting from 2-C-formyl galactal and 2-C-formyl glucal, reacting with various 4-hydroxycoumarins in a very short reaction time (10 min) under microwave assisted conditions. The anticancer activity of these synthesized pyrano[3,2-c]pyranones was determined in detail through cellular assays against MCF-7 (breast), MDA-MB-231 (breast) and HepG2 (liver) cancer cell lines. The newly synthesized pyrano[3,2-c]pyranones were screened for their cell-viability and anti-proliferative activity against MCF-7, MDA-MB-231 and HepG2 cell lines. Compounds 12, 13 and 14 exhibited high growth inhibitory potencies selectively against MCF-7 cells with half-maximal inhibitory concentration (IC50) values of 19.9, 14.5 and 10.9 μM respectively. Compounds 12, 13, 14, 15 and 19 inhibited the growth of MDA-MB-231 cells (breast) by 43, 44, 37, 31 and 45% respectively. However, no inhibitory effect was observed for these compounds in the human liver cancer cell line (HepG2) and normal cell lines (HEK293, human embryonic kidney cells). Mechanistic studies showed that these compounds alter the cell morphology and cause G2/M arrest in MCF-7. Further studies showed that compounds 12, 13 and 14 significantly inhibited cell migration which was accompanied by altered microtubule distribution. An enhanced accumulation of these compounds in cells was observed as compared to the 4-hydroxycoumarins precursor in the intracellular uptake assay. These findings confirm that carbohydrate fused pyrano[3,2-c]pyranones are better candidates for anticancer activity.
