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Heinz Wolf - One of the best experts on this subject based on the ideXlab platform.
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etoposide a new approach to the synthesis of 4 o 2 amino 2 deoxy 4 6 o ethylidene β d glucopyranosyl 4 o demethyl 4 Epipodophyllotoxin
Carbohydrate Research, 1990Co-Authors: Cenek Kolar, Konrad Dehmel, Heinz WolfAbstract:Abstract Synthesis of 3- O -acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α-( 7 α) and -β- d -glucopyranose ( 7 β) and their 3- O -chloroacetyl analogues ( 11 α and 11 β) are described. Condensation (BF 3 -etherate, ethyl acetate, −20°) of 7 α with 4′- O -benzyloxycarbonyl-4′- O -demethyl-4-Epipodophyllotoxin ( 8 ) afforded mainly the β-glycoside 9 β (α,β-ratio 1:9). Condensation of 11 αβ with 8 or the 4′- O -chloroacetyl analogue 13 gave mainly the 4- O -(2-benzyloxycarbonylamino-3- O -chloroacetyl-2-deoxy-4,6- O -ethylidene-β- d -glucopyranosyl)- Epipodophyllotoxin 12 β or 15 β. Glycosidation of podophyllotoxin ( 14 ) with 11 αβ (during which the aglycon epimerized at C-4 under the action of BF 3 -etherate) afforded α- ( 16 α) and β-glycoside ( 16 β) in the ratio 1:5. Removal of the chloroacetyl groups from 12 β, its α analogue 12 α, and 15 β gave the 4- O -(2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α- ( 17 α) and -β- d -glucopyranosyl)-4′- O -demethyl-Epipodophyllotoxins ( 17 β and 20 β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4- O -(2-amino-2-deoxy-4,6- O -ethylidene-α- ( 18 α) and -β- d -glucopyranosyl)-4′- O -demethyl-4-Epipodophyllotoxin ( 18 β). Reductive alkylation of 18 β and 18 α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19 α.
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Etoposide: a new approach to the synthesis of 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-β-d-glucopyranosyl)-4′-O-demethyl-4-Epipodophyllotoxin
Carbohydrate Research, 1990Co-Authors: Cenek Kolar, Konrad Dehmel, Heinz WolfAbstract:Abstract Synthesis of 3- O -acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α-( 7 α) and -β- d -glucopyranose ( 7 β) and their 3- O -chloroacetyl analogues ( 11 α and 11 β) are described. Condensation (BF 3 -etherate, ethyl acetate, −20°) of 7 α with 4′- O -benzyloxycarbonyl-4′- O -demethyl-4-Epipodophyllotoxin ( 8 ) afforded mainly the β-glycoside 9 β (α,β-ratio 1:9). Condensation of 11 αβ with 8 or the 4′- O -chloroacetyl analogue 13 gave mainly the 4- O -(2-benzyloxycarbonylamino-3- O -chloroacetyl-2-deoxy-4,6- O -ethylidene-β- d -glucopyranosyl)- Epipodophyllotoxin 12 β or 15 β. Glycosidation of podophyllotoxin ( 14 ) with 11 αβ (during which the aglycon epimerized at C-4 under the action of BF 3 -etherate) afforded α- ( 16 α) and β-glycoside ( 16 β) in the ratio 1:5. Removal of the chloroacetyl groups from 12 β, its α analogue 12 α, and 15 β gave the 4- O -(2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α- ( 17 α) and -β- d -glucopyranosyl)-4′- O -demethyl-Epipodophyllotoxins ( 17 β and 20 β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4- O -(2-amino-2-deoxy-4,6- O -ethylidene-α- ( 18 α) and -β- d -glucopyranosyl)-4′- O -demethyl-4-Epipodophyllotoxin ( 18 β). Reductive alkylation of 18 β and 18 α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19 α.
Zhiyan Xiao - One of the best experts on this subject based on the ideXlab platform.
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Antitumor agents. 234. Design, synthesis, and biological evaluation of novel 4β-[(4″-benzamido)-amino]-4′-O-demethyl- Epipodophyllotoxin derivatives
Journal of Medicinal Chemistry, 2004Co-Authors: Zhiyan Xiao, Hui Kang Wang, Kenneth F Bastow, John R. Vance, Robert S Sidwell, Ming S ChenAbstract:A series of 4β-[(4‘ ‘-benzamido)-amino]-4‘-O-demethyl-Epipodophyllotoxin derivatives (11−23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13−18, 20−22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C4-modified new derivatives exhibi...
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antitumor agents 234 design synthesis and biological evaluation of novel 4β 4 benzamido amino 4 o demethyl Epipodophyllotoxin derivatives
Journal of Medicinal Chemistry, 2004Co-Authors: Zhiyan Xiao, Hui Kang Wang, Kenneth F Bastow, John R. Vance, Robert S Sidwell, Ming S ChenAbstract:A series of 4β-[(4‘ ‘-benzamido)-amino]-4‘-O-demethyl-Epipodophyllotoxin derivatives (11−23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13−18, 20−22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C4-modified new derivatives exhibi...
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Antitumor agents. Part 227: Studies on novel 4′-O-demethyl- Epipodophyllotoxins as antitumor agents targeting topoisomerase II
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Zhiyan Xiao, Kenneth F Bastow, John R. VanceAbstract:Abstract Eight novel Epipodophyllotoxin derivatives ( 6 – 13 ), which were designed to overcome drug resistance and enhance topoisomerase II inhibition, were synthesized and evaluated. Two of these compounds ( 7 and 8 ) showed better preclinical activity profiles, including cell growth inhibition, cell killing, and in vitro topoisomerase II inhibition, as compared to the prototype molecule etoposide ( 1 ). They also retained the superior drug-resistance profile of GL-331 ( 4 ), an Epipodophyllotoxin derivative currently in clinical evaluation.
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antitumor agents 213 modeling of Epipodophyllotoxin derivatives using variable selection k nearest neighbor qsar method
Journal of Medicinal Chemistry, 2002Co-Authors: Zhiyan Xiao, Yunde Xiao, Jun Feng, Alexander Golbraikh, And Alexander TropshaAbstract:We have applied a variable selection k nearest neighbor quantitative structure-activity relationship (kNN QSAR) method to develop predictive QSAR models for 157 Epipodophyllotoxins synthesized previously in our ongoing effort to develop potential anticancer agents. QSAR models were generated using multiple topological descriptors of chemical structures, including molecular connectivity indices (MCI) and molecular operating environment descriptors. The 157 compounds were separated into several training and test sets. The robustness of QSAR models was characterized by the values of the internal leave one out cross-validated R 2 (q 2 ) for the training set and external predictive R 2 for the test set. The significance of the training set models was confirmed by statistically higher values of q 2 for the original data set as compared to q 2 values for the same data set with randomly shuffled activities, kNN QSAR models were compared with those obtained with the comparative molecular field analysis method; the kNN QSAR approach afforded models with higher values of both q 2 and predictive R 2 . One of the best models obtained from kNN analysis using MCI as descriptors provided q 2 and predictive R 2 values of 0.60 and 0.62, respectively. QSAR models developed in these studies shall aid in future design of novel potent Epipodophyllotoxin derivatives.
Cenek Kolar - One of the best experts on this subject based on the ideXlab platform.
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etoposide a new approach to the synthesis of 4 o 2 amino 2 deoxy 4 6 o ethylidene β d glucopyranosyl 4 o demethyl 4 Epipodophyllotoxin
Carbohydrate Research, 1990Co-Authors: Cenek Kolar, Konrad Dehmel, Heinz WolfAbstract:Abstract Synthesis of 3- O -acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α-( 7 α) and -β- d -glucopyranose ( 7 β) and their 3- O -chloroacetyl analogues ( 11 α and 11 β) are described. Condensation (BF 3 -etherate, ethyl acetate, −20°) of 7 α with 4′- O -benzyloxycarbonyl-4′- O -demethyl-4-Epipodophyllotoxin ( 8 ) afforded mainly the β-glycoside 9 β (α,β-ratio 1:9). Condensation of 11 αβ with 8 or the 4′- O -chloroacetyl analogue 13 gave mainly the 4- O -(2-benzyloxycarbonylamino-3- O -chloroacetyl-2-deoxy-4,6- O -ethylidene-β- d -glucopyranosyl)- Epipodophyllotoxin 12 β or 15 β. Glycosidation of podophyllotoxin ( 14 ) with 11 αβ (during which the aglycon epimerized at C-4 under the action of BF 3 -etherate) afforded α- ( 16 α) and β-glycoside ( 16 β) in the ratio 1:5. Removal of the chloroacetyl groups from 12 β, its α analogue 12 α, and 15 β gave the 4- O -(2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α- ( 17 α) and -β- d -glucopyranosyl)-4′- O -demethyl-Epipodophyllotoxins ( 17 β and 20 β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4- O -(2-amino-2-deoxy-4,6- O -ethylidene-α- ( 18 α) and -β- d -glucopyranosyl)-4′- O -demethyl-4-Epipodophyllotoxin ( 18 β). Reductive alkylation of 18 β and 18 α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19 α.
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Etoposide: a new approach to the synthesis of 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-β-d-glucopyranosyl)-4′-O-demethyl-4-Epipodophyllotoxin
Carbohydrate Research, 1990Co-Authors: Cenek Kolar, Konrad Dehmel, Heinz WolfAbstract:Abstract Synthesis of 3- O -acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α-( 7 α) and -β- d -glucopyranose ( 7 β) and their 3- O -chloroacetyl analogues ( 11 α and 11 β) are described. Condensation (BF 3 -etherate, ethyl acetate, −20°) of 7 α with 4′- O -benzyloxycarbonyl-4′- O -demethyl-4-Epipodophyllotoxin ( 8 ) afforded mainly the β-glycoside 9 β (α,β-ratio 1:9). Condensation of 11 αβ with 8 or the 4′- O -chloroacetyl analogue 13 gave mainly the 4- O -(2-benzyloxycarbonylamino-3- O -chloroacetyl-2-deoxy-4,6- O -ethylidene-β- d -glucopyranosyl)- Epipodophyllotoxin 12 β or 15 β. Glycosidation of podophyllotoxin ( 14 ) with 11 αβ (during which the aglycon epimerized at C-4 under the action of BF 3 -etherate) afforded α- ( 16 α) and β-glycoside ( 16 β) in the ratio 1:5. Removal of the chloroacetyl groups from 12 β, its α analogue 12 α, and 15 β gave the 4- O -(2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α- ( 17 α) and -β- d -glucopyranosyl)-4′- O -demethyl-Epipodophyllotoxins ( 17 β and 20 β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4- O -(2-amino-2-deoxy-4,6- O -ethylidene-α- ( 18 α) and -β- d -glucopyranosyl)-4′- O -demethyl-4-Epipodophyllotoxin ( 18 β). Reductive alkylation of 18 β and 18 α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19 α.
Konrad Dehmel - One of the best experts on this subject based on the ideXlab platform.
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etoposide a new approach to the synthesis of 4 o 2 amino 2 deoxy 4 6 o ethylidene β d glucopyranosyl 4 o demethyl 4 Epipodophyllotoxin
Carbohydrate Research, 1990Co-Authors: Cenek Kolar, Konrad Dehmel, Heinz WolfAbstract:Abstract Synthesis of 3- O -acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α-( 7 α) and -β- d -glucopyranose ( 7 β) and their 3- O -chloroacetyl analogues ( 11 α and 11 β) are described. Condensation (BF 3 -etherate, ethyl acetate, −20°) of 7 α with 4′- O -benzyloxycarbonyl-4′- O -demethyl-4-Epipodophyllotoxin ( 8 ) afforded mainly the β-glycoside 9 β (α,β-ratio 1:9). Condensation of 11 αβ with 8 or the 4′- O -chloroacetyl analogue 13 gave mainly the 4- O -(2-benzyloxycarbonylamino-3- O -chloroacetyl-2-deoxy-4,6- O -ethylidene-β- d -glucopyranosyl)- Epipodophyllotoxin 12 β or 15 β. Glycosidation of podophyllotoxin ( 14 ) with 11 αβ (during which the aglycon epimerized at C-4 under the action of BF 3 -etherate) afforded α- ( 16 α) and β-glycoside ( 16 β) in the ratio 1:5. Removal of the chloroacetyl groups from 12 β, its α analogue 12 α, and 15 β gave the 4- O -(2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α- ( 17 α) and -β- d -glucopyranosyl)-4′- O -demethyl-Epipodophyllotoxins ( 17 β and 20 β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4- O -(2-amino-2-deoxy-4,6- O -ethylidene-α- ( 18 α) and -β- d -glucopyranosyl)-4′- O -demethyl-4-Epipodophyllotoxin ( 18 β). Reductive alkylation of 18 β and 18 α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19 α.
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Etoposide: a new approach to the synthesis of 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-β-d-glucopyranosyl)-4′-O-demethyl-4-Epipodophyllotoxin
Carbohydrate Research, 1990Co-Authors: Cenek Kolar, Konrad Dehmel, Heinz WolfAbstract:Abstract Synthesis of 3- O -acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α-( 7 α) and -β- d -glucopyranose ( 7 β) and their 3- O -chloroacetyl analogues ( 11 α and 11 β) are described. Condensation (BF 3 -etherate, ethyl acetate, −20°) of 7 α with 4′- O -benzyloxycarbonyl-4′- O -demethyl-4-Epipodophyllotoxin ( 8 ) afforded mainly the β-glycoside 9 β (α,β-ratio 1:9). Condensation of 11 αβ with 8 or the 4′- O -chloroacetyl analogue 13 gave mainly the 4- O -(2-benzyloxycarbonylamino-3- O -chloroacetyl-2-deoxy-4,6- O -ethylidene-β- d -glucopyranosyl)- Epipodophyllotoxin 12 β or 15 β. Glycosidation of podophyllotoxin ( 14 ) with 11 αβ (during which the aglycon epimerized at C-4 under the action of BF 3 -etherate) afforded α- ( 16 α) and β-glycoside ( 16 β) in the ratio 1:5. Removal of the chloroacetyl groups from 12 β, its α analogue 12 α, and 15 β gave the 4- O -(2-benzyloxycarbonylamino-2-deoxy-4,6- O -ethylidene-α- ( 17 α) and -β- d -glucopyranosyl)-4′- O -demethyl-Epipodophyllotoxins ( 17 β and 20 β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4- O -(2-amino-2-deoxy-4,6- O -ethylidene-α- ( 18 α) and -β- d -glucopyranosyl)-4′- O -demethyl-4-Epipodophyllotoxin ( 18 β). Reductive alkylation of 18 β and 18 α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19 α.
Ming S Chen - One of the best experts on this subject based on the ideXlab platform.
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Antitumor agents. 234. Design, synthesis, and biological evaluation of novel 4β-[(4″-benzamido)-amino]-4′-O-demethyl- Epipodophyllotoxin derivatives
Journal of Medicinal Chemistry, 2004Co-Authors: Zhiyan Xiao, Hui Kang Wang, Kenneth F Bastow, John R. Vance, Robert S Sidwell, Ming S ChenAbstract:A series of 4β-[(4‘ ‘-benzamido)-amino]-4‘-O-demethyl-Epipodophyllotoxin derivatives (11−23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13−18, 20−22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C4-modified new derivatives exhibi...
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antitumor agents 234 design synthesis and biological evaluation of novel 4β 4 benzamido amino 4 o demethyl Epipodophyllotoxin derivatives
Journal of Medicinal Chemistry, 2004Co-Authors: Zhiyan Xiao, Hui Kang Wang, Kenneth F Bastow, John R. Vance, Robert S Sidwell, Ming S ChenAbstract:A series of 4β-[(4‘ ‘-benzamido)-amino]-4‘-O-demethyl-Epipodophyllotoxin derivatives (11−23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13−18, 20−22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C4-modified new derivatives exhibi...