50425-06-4Relevant academic research and scientific papers
AMINOALYL-IMIDAZOTETRAZINES FOR TREATMENT OF CANCER
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Page/Page column 38, (2009/12/02)
The present invention relates to imidazotetrazines of Formula (I) and their use in the treatment of cancer.
Synthesis and structure-activity relationships for 2,4-dinitrobenzamide-5- mustards as prodrugs for the Escherichia coli nfsB nitroreductase in gene therapy
Atwell, Graham J.,Yang, Shangjin,Pruijn, Frederik B.,Pullen, Susan M.,Hogg, Alison,Patterson, Adam V.,Wilson, William R.,Denny, William A.
, p. 1197 - 1212 (2007/10/03)
A series of 2,4-dinitrobenzamide mustards were prepared from 5-chloro-2,4-dinitrobenzoic acid or the corresponding 5-dimesylate mustard as potential prodrugs for gene-directed enzyme prodrug therapy (GDEPT) with the E. coli nfsB nitroreductase (NTR). The compounds, including 32 new examples, were evaluated in four pairs of NTR+ve/-ve cell lines for selective cytotoxicity (IC50 and IC50 ratios), in multicellular layer (MCL) cultures for bystander effects, and for in vivo activity against tumors grown from stably NTR transfected EMT6 and WiDr cells in nude mice. Multivariate regression analysis of the IC50 results was undertaken using a partial least-squares projection to latent structures model. In NTR -ve lines, cytotoxicity correlated positively with logP, negatively with hydrogen bond acceptors (HA) and donors (HD) in the amide side chain, and positively with the reactivity of the less-reactive leaving group of the mustard function, likely reflecting toxicity due to DNA monoadducts. Potency and selectivity for NTR+ve lines was increased by logP and HD, decreased by HA, and was positively correlated with the leaving group efficiency of the more-reactive group, likely reflecting DNA crosslinking. NTR selectivity was greatest for asymmetric chloro/ mesylate and bromo/mesylate mustards. Bystander effects in the MCL assay also correlated positively with logP and negatively with leaving group reactivity, presumably reflecting the transcellular diffusion/reaction properties of the activated metabolites. A total of 18 of 22 mustards showed equal or greater bystander efficiencies in MCLs than the aziridinylbenzamide CB 1954, which is currently in clinical trial for NTR-GDEPT. The dibromo and bromomesylate mustards were surprisingly well tolerated in mice. High MTD/ IC50 (NTR+ve) ratios translated into curative activity of several compounds against NTR+ve tumors. A bromomesylate mustard showed superior activity against WiDr tumors grown from 1:9 mixtures of NTR+ve and NTR-ve cells, indicating a strong bystander effect in vivo.
Aziridinyldinitrobenzamides: Synthesis and structure-activity relationships for activation by E. coli nitroreductase
Helsby, Nuala A.,Atwell, Graham J.,Yang, Shangjin,Palmer, Brian D.,Anderson, Robert F.,Pullen, Susan M.,Ferry, Dianne M.,Hogg, Alison,Wilson, William R.,Denny, William A.
, p. 3295 - 3307 (2007/10/03)
The 5-aziridinyl-2,4-dinitrobenzamide CB 1954 is a substrate for the oxygen-insensitive nitroreductase (NTR) from E. coli and is in clinical trial in combination with NTR-armed adenoviral vectors in a GDEPT protocol; CB 1954 is also of interest for selective deletion of NTR-marked cells in normal tissues. Since little further drug development has been carried out around this lead, we report here the synthesis of more soluble variants and regioisomers and structure-activity relationship (SAR) studies. The compounds were primarily prepared from the corresponding chloro(di)nitroacids through amide side chain elaboration and subsequent aziridine formation. One-electron reduction potentials [E(1)], determined by pulse radiolysis, were around -400 mV, varying little for aziridinyldinitrobenzamide regioisoiners. Cytotoxicity in a panel of NTR-transfected cell lines showed that in the CB 1954 series there was considerable tolerance of substituted CONHR side chains. The isomeric 2-aziridinyl-3,5-dinitrobenzamide was also selective toward NTR+ve lines but was approximately 10-fold less potent than CB 1954. Other regioisomers were too insoluble to evaluate. While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site. CB 1954 is also a substrate for the two-electron reductase DT-diaphorase, but all of the other aziridines (regioisomers and close analogues) were poorer substrates with resulting improved specificity for NTR. Bystander effects were determined in multicellular layer cocultures and showed that the more hydrophilic side chains resulted in a modest reduction in bystander killing efficiency. A limited number of analogues were tested for in vivo activity, using a single ip dose to CD-1 nude mice bearing WiDr-NTRneo tumors. The most active of the CB 1954 analogues was a diol derivative, which showed a substantial median tumor growth delay (59 days compared with >85 days for CB 1954) in WiDr xenografts comprising 50% NTR+ve cells. The diol is much more soluble and can be formulated in saline for administration. The results suggest there may be advantages with carefully selected analogues of CB 1954; the weaker bystander effect of its diol derivative may be an advantage in the selective cell ablation of NTR-tagged cells in normal tissues.
Nitrophenylaziridine compounds and their use as prodrugs
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, (2008/06/13)
A range of aziridin-1-yl nitrobenzamides are provided for use as prodrugs in conjunction with nitroreductase (NR) enzymes. The amides may have 1 or 2-substituents which may be bulky and polar. For example, 5-(aziridin-1-yl)-N-[2-(4-morpholino)ethyl]-2,4-d
N-3-substituted imidazoquinazolinones: Potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction
Rotella, David P.,Sun, Zhong,Zhu, Yeheng,Krupinski, John,Pongrac, Ronald,Seliger, Laurie,Normandin, Diane,Macor, John E.
, p. 1257 - 1263 (2007/10/03)
Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describe
Mustard prodrugs for activation by Escherichia coli nitroreductase in gene-directed enzyme prodrug therapy
Friedlos, Frank,Denny, William A.,Palmer, Brian D.,Springer, Caroline J.
, p. 1270 - 1275 (2007/10/03)
Twenty nitrogen mustard analogues derived from 5-(aziridin-l-yl)-2,4- dinitrobenzamide (CB 1954, 1) were evaluated as candidate prodrugs for gene- directed enzyme prodrug therapy (GDEPT) in Chinese hamster V79 cell lines engineered to express Escherichia
Hypoxia-Selective Antitumor Agents. 5. Synthesis of Water-Soluble Nitroaniline Mustards with Selective Cytotoxicity for Hypoxic Mammalian Cells
Palmer, Brian D.,Wilson, William R.,Cliffe, Stephen,Denny, William A.
, p. 3214 - 3222 (2007/10/02)
Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine.However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E1/2 ca. -600mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction.To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines.The N-carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the noncarboxamide compounds, were still low and little selectivity for hypoxic cells were observed.A series of carboxamides of 2,4-dinitroaniline mustard was also prepared.These compounds had reduction potentials in the desired range (E1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells.The most selective compounds were 5--2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-carboxamide analogue.These showed selectivities of 60- to 70-fold for hypoxic UV4 cells.The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system.Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase).Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for the its higher hypoxic selectivity than that of 23.
