- Practical bromination of arylhydroxylamines with SOBr2 towards ortho-bromo-anilides
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A facile approach for synthesizing ortho-bromoanilides from readily available aryhydroxylamines and thionyl bromide is demonstrated in this work. Mild reaction conditions and broad scope of substrates ranging from heterocyclic structures to pharmaceutics-potential motifs are used in the reactions of this paper. Efficient bromination of ortho C–H bonds of the aryhydroxylamines has been achieved. Ortho-bromoanilide products were obtained in good to excellent yields, and model scaled-up reactions of this synthetic approach are shown in this work.
- Du, Yuanbo,Feng, Lei,Gao, Hongyin,Guo, Lirong,Lu, Haifeng,Xi, Zhenguo
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supporting information
(2021/05/19)
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- Optimised synthesis of a nitroCBI hypoxia-activated prodrug with substantial anticancer activity
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An optimised synthesis of a hypoxia-activated anticancer prodrug related to the duocarmycin family of natural products is described. The improved 10-step synthesis increases the overall yield from 4.4% to over 40% while requiring just 2 chromatography-bas
- Lee, Ho H.,Dickson, Benjamin D.,Stevenson, Ralph J.,Yang, Shangjin,Tercel, Moana
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p. 3001 - 3007
(2019/05/01)
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- Substituted benzoquinazolinones. Part 2: Synthesis of amino-, and sulfanyl-derivatives of benzo[f]- and benzo[h]quinazolinones
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Amino- and sulfanyl-derivatives of benzoquinazolinones 16a-c, 20a-c and 21a-c were prepared under palladium-catalyzed Buchwald-Hartwig coupling reaction using bromobenzoquinazolinones 15, 19a, 19b and 1-substituted piperazines or mercaptans. The combination of Pd(OAc)2 with XantPhos proved to be the best for these conversions in the presence of KOt-Bu, in 1,4-dioxane as a solvent, at 90-100 °C. The 8-bromobenzo[f]quinazolin-1(2H)-one 15 was synthesized via condensation of the ethyl or tert-butyl 2-amino-8-bromonaphthalene-1-carboxylate 6, 10 with formamide, followed by reaction with 3,4-dimethoxybenzyl bromide. However, the 6-bromobenzo[h]quinazolin-4(3H)-ones 19a, 19b were prepared from ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]naphthalene-2-carboxylate (17). Biological screening of the potential cytotoxicity of compounds 16a, 20a, 20c on HT29 and HCT116 cell lines, has shown that compound 20a has a significant anticancer activity.
- Nowak, Monika,Malinowski, Zbigniew,Fornal, Emilia,Jó?wiak, Andrzej,Parfieniuk, Ewa,Gajek, Gabriela,Kontek, Renata
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p. 9463 - 9473
(2015/11/18)
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- Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity
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A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds w
- Sheldrake, Helen M.,Travica, Sandra,Johansson, Inger,Loadman, Paul M.,Sutherland, Mark,Elsalem, Lina,Illingworth, Nicola,Cresswell, Alexander J.,Reuillon, Tristan,Shnyder, Steven D.,Mkrtchian, Souren,Searcey, Mark,Ingelman-Sundberg, Magnus,Patterson, Laurence H.,Pors, Klaus
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p. 6273 - 6277
(2013/09/02)
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- CBI DERIVATIVES SUBJECT TO REDUCTIVE ACTIVATION
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A unique class of N-acyl O-amino phenol prodrugs of CBI-TMI and CBI-indole2 were synthesized and shown to be prodrugs, subject to reductive activation by nucleophilic cleavage of a weak N-O bond, effectively releasing the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Most impressively, assessment of the in vivo antitumor activity of a representative O- (acylamino) prodrug, 8, indicate that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that the inactive prodrugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.
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- Hypoxia-activated prodrugs: Substituent effects on the properties of nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) prodrugs of DNA minor groove alkylating agents
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Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively tox
- Tercel, Moana,Atwell, Graham J.,Yang, Shangjin,Stevenson, Ralph J.,Botting, K. Jane,Boyd, Maruta,Smith, Eileen,Anderson, Robert F.,Denny, William A.,Wilson, William R.,Pruijn, Frederik B.
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experimental part
p. 7258 - 7272
(2010/07/13)
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- A unique class of duocarmycin and CC-1065 analogues subject to reductive activation
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N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.
- Jin, Wei,Trzupek, John D.,Rayl, Thomas J.,Broward, Melinda A.,Vielhauer, George A.,Weir, Scott J.,Hwang, Inkyu,Boger, Dale L.
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p. 15391 - 15397
(2008/09/18)
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- NITROBENZINDOLES AND THEIR USE IN CANCER THERAPY
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The present invention relates generally to nitro-1,2-dihydro-3H-benzo[e]indoles and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation a
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Page/Page column 44-47
(2010/11/08)
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