- Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs
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A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged us a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.
- Duan, Jian-Xin,Jiao, Hailong,Kaizerman, Jacob,Stanton, Timothy,Evans, James W.,Lan, Leslie,Lorente, Gustavo,Banica, Monica,Jung, Don,Wang, Jinwei,Ma, Huaiyu,Li, Xiaoming,Yang, Zhijian,Hoffman, Robert M.,Ammons, W. Steve,Hart, Charles P.,Matteucci, Mark
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- Hydrolytic pathway of glufosfamide, a new phosphorylated anticancer agent
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31P NMR was used to demonstrate that glufosfamide is hydrolyzed into isophosphoramide mustard (IPM) with a half-life of about 25 h at 37°C and pH 7.4 in buffer as well as in human plasma. Through a cascade of reactions, IPM gives rise to three
- De Rouveze, Marie-Caroline Aoust,Gilard, Veronique,Martino, Robert,Malet-Martino, Myriam,Niemeyer, Ulf
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- Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy
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The tumor microenvironment in chondrosarcoma (CHS), a chemo- and radio-resistant cancer provides unique hallmarks for developing a chondrosarcoma targeted drug‐delivery system. Tumor targeting could be achieved using a quaternary ammonium function (QA) as a ligand for aggrecan, the main high negative charged proteoglycan of the extracellular matrix of CHS, and a 2-nitroimidazole as trigger that enables hypoxia‐responsive drug release. In a previous work, ICF05016 was identified as efficient proteoglycan-targeting hypoxia-activated prodrug in a human extraskeletal myxoid chondrosarcoma model in mice and a first study of the structure-activity relationship of the QA function and the alkyl linker length was conducted. Here, we report the second part of the study, namely the modification of the nitro-aromatic trigger and the position of the proteoglycan-targeting ligand at the aromatic ring as well as the nature of the alkylating mustard. Synthetic approaches have been established to functionalize the 2-nitroimidazole ring at the N-1 and C-4 positions with a terminal tertiary alkyl amine, and to perform the phosphorylation step namely through the use of an amine borane complex, leading to phosphoramide and isophosphoramide mustards and also to a phosphoramide mustard bearing four 2-chloroethyl chains. In a preliminary study using a reductive chemical activation, QA-conjugates, except the 4-nitrobenzyl one, were showed to undergo efficient cleavage with release of the corresponding mustard. However N,N,N-trimethylpropylaminium tethered to the N-1 or C-4 positions of the imidazole seemed to hamper the enzymatic reduction of the prodrugs and all tested compounds featured moderate selectivity toward hypoxic cells, likely not sufficient for application as hypoxia-activated prodrugs.
- Canitrot, Damien,Chezal, Jean-Michel,Galmier, Marie-Josephe,Gaumet, Vincent,Gerard, Yvain,Ghedira, Donia,Maubert, Elise,Miot-Noirault, Elisabeth,Peyrode, Caroline,Tarrit, Sebastien,Voissière, Aurélien,Weber, Valérie
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supporting information
(2020/04/08)
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- SALTS OF ISOPHOSPHORAMIDE MUSTARD AND ANALOGS THEREOF AS ANTI-TUMOR AGENTS
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The present disclosure relates to salts and compositions of isophosphoramide mustard and isophosphoramide mustard analogs. In one embodiment the salts can be represented by the formula wherein A+ represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines; and X and Y independently represent leaving groups. Also disclosed herein are methods for making such compounds and formulating pharmaceutical compositions thereof. Methods for administering the disclosed compounds to subjects, particularly to treat hyperproliferative disorders, also are disclosed.
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- TREATMENT OR PROPHYLAXIS OF PROLIFERATIVE CONDITIONS
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The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.
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Page/Page column 36
(2010/11/17)
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- SYNTHESIS AND FORMULATIONS OF SALTS OF ISOPHOSPHORAMIDE MUSTARD AND ANALOGS THEREOF
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Disclosed herein are formulations and methods of manufacture of compounds of formula (E):wherein X and Y independently represent leaving groups; and A+ is an ammonium cation.
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Page/Page column 44
(2010/04/03)
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- PHOSPHORAMIDATE ALKYLATOR PRODRUGS
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Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.
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Page/Page column 125-126
(2008/06/13)
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- Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents
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The present disclosure relates to salts and compositions of isophosphoramide mustard and isophosphoramide mustard analogs. In one embodiment the salts can be represented by the formula wherein A+ represents an ammonium species selected from the
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Page/Page column 7
(2008/06/13)
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- Glutathione conjugation of the cytostatic drug ifosfamide and the role of human glutathione S-transferases
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Development of drug resistance against alkylating cytostatic drugs has been associated with higher intracellular concentrations of glutathione (GSH) and increased expression of glutathione S-transferase (GST) enzymes. Therefore, enhanced detoxification by the glutathione/glutathione S- transferase pathway has been proposed as a major factor in the development of drug resistance toward alkylating agents. In this paper we describe 31P NMR and HPLC studies on the spontaneous and glutathione S-transferase catalyzed formation of glutathionyl conjugates of two metabolites of ifosfamide, i.e., 4-hydroxyifosfamide and ifosfamide mustard. At 25 °C activated ifosfamide (=4-hydroxyifosfamide + aldoifosfamide) disappeared faster in the presence of a 10-fold excess of GSH (t( 1/2 ) = 107 min) compared to incubations without GSH (t( 1/2 ) = 266 min). No evidence for the formation of 4-glutathionyl ifosfamide was found. The ultimate alkylating species of ifosfamide is ifosfamide mustard (IM). In the absence of glutathione, the rate constant for the disappearance of the ifosfamide mustard signal at 25 °C (pH 7) was 1.98 x 10-3 min-1 (t( 1/2 ) = 350 min). In the presence of a 10-fold molar excess of glutathione, this rate constant was 1.95 x 10-3 min-1 (t( 1/2 ) = 355 min), indicating that the spontaneous formation of an aziridinium ion is the rate-limiting event in the reaction with glutathione. The aziridinium ion formed from IM can deprotonate upon formation, leading to the formation of a (noncharged) aziridine species. This intermediate (N-(2-chloroethyl)-N' phosphoric acid diamide) was characterized by 31P, 1H, and 13C NMR spectra. When 2 mM ifosfamide mustard was incubated with 1 mM GSH in the presence of 40 μM GST P1-1, the formation of monoglutathionyl ifosfamide mustard was 2.3-fold increased above the spontaneous level. The other major human isoenzymes tested (A1-1, A2-2, and M1a-1a) did not influence the formation of monoglutathionyl ifosfamide mustard. The results of these studies demonstrate that increased levels of GST P1-1 can contribute to an enhanced detoxification of ifosfamide.
- Dirven,Megens,Oudshoorn,Dingemanse,Van Ommen,Van Bladeren
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p. 979 - 986
(2007/10/03)
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- 31P NMR Studies of the Kinetics of Bisalkylation by Isophosphoramide Mustard: Comparisons with Phosphoramide Mustard
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31P nuclear magnetic resonance spectroscopy was used to measure the pKa (4.28 +/- 0.2) of isophosphoramide mustard (IPM) at 20 deg C and to study the kinetics and products of the decomposition of IPM at a solution pH value of ca. 7.4 and at temperatures between 20 and 47 deg C in the presence of nucleophilic trapping agents.At 37 deg C, the half-life for the first alkylation was ca. 77 min and ca. 171 min for the second alkylation; these data may be compared with those for phosphoramide mustard (Engle, T.W.; Zon, G.; Egan, W.J.Med.Chem. 1982, 25, 1347), wherein the half-lives for the first and second alkylations are approximately the same (18 min).The rate of fragmentation of aldoifosfamide to IPM and acrolein was also studied by NMR spectroscopy (pH 7.0; 37 deg C; 0.07 M phosphate); under the noted conditions, the half-life of aldoifosfamide was fouund to be ca. 60 min.
- Boal, Jila H.,Williamson, Margaret,Boyd, Victoria L.,Ludeman, Susan M.,Egan, William
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p. 1768 - 1773
(2007/10/02)
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