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Biochemical Pharmacology Aug 1973
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Bile; Chromatography, Thin Layer; In Vitro Techniques; Isotope Labeling; Magnesium Sulfate; Male; Mass Spectrometry; Nitrogen Mustard Compounds; Rats; Solubility; Solvents; Tritium
PubMed: 4726563
DOI: 10.1016/0006-2952(73)90079-8 -
Chemistry (Weinheim An Der Bergstrasse,... Nov 2015A new G-quadruplex (G-4)-directing alkylating agent BMVC-C3M was designed and synthesized to integrate 3,6-bis(1-methyl-4-vinylpyridinium iodide)carbazole (BMVC) with...
A new G-quadruplex (G-4)-directing alkylating agent BMVC-C3M was designed and synthesized to integrate 3,6-bis(1-methyl-4-vinylpyridinium iodide)carbazole (BMVC) with aniline mustard. Various telomeric G-4 structures (hybrid-2 type and antiparallel) and an oncogene promoter, c-MYC (parallel), were constructed to react with BMVC-C3M, yielding 35 % alkylation yield toward G-4 DNA over other DNA categories (<6 %) and high specificity under competition conditions. Analysis of the intact alkylation adducts by electrospray ionization mass spectroscopy (ESI-MS) revealed the stepwise DNA alkylation mechanism of aniline mustard for the first time. Furthermore, the monoalkylation sites and intrastrand cross-linking sites were determined and found to be dependent on G-4 topology based on the results of footprinting analysis in combination with mass spectroscopic techniques and in silico modeling. The results indicated that BMVC-C3M preferentially alkylated at A15 (H26), G12 (H24), and G2 (c-MYC), respectively, as monoalkylated adducts and formed A15-C3M-A21 (H26), G12-C3M-G4 (H24), and G2-C3M-G4/G17 (c-MYC), respectively, as cross-linked dialkylated adducts. Collectively, the stability and site-selective cross-linking capacity of BMVC-C3M provides a credible tool for the structural and functional characterization of G-4 DNAs in biological systems.
Topics: Alkylation; Aniline Mustard; Carbazoles; DNA; G-Quadruplexes; Hydrocarbons, Iodinated; Pyridinium Compounds
PubMed: 26769627
DOI: 10.1002/chem.201502595 -
Current Pharmaceutical Design 2002Nitroreductases that metabolise aromatic nitro groups to hydroxylamines are attractive as enzymes for GDEPT because of the very large electronic change that this... (Review)
Review
Nitroreductases that metabolise aromatic nitro groups to hydroxylamines are attractive as enzymes for GDEPT because of the very large electronic change that this metabolism generates, providing an efficient switch that can be exploited to generate potent cytotoxins. While nitroreductase enzymes are widespread, nearly all the work using these in GDEPT has been with the nfsB gene product of Escherichia coli, an oxygen-insensitive flavin mononucleotide nitroreductase (NTR). Four classes of prodrugs for NTR have been described; dinitroaziridinylbenzamides, dinitrobenzamide mustards, 4-nitrobenzylcarbamates and nitroindolines. While some quinones are excellent substrates for NTR, none have been identified as potential GDEPT prodrugs. The most widely studied prodrug used for GDEPT in conjunction with NTR is the dinitroaziridinylbenzamide CB 1954. This shows high selectivity (>1000-fold) in cell lines transfected with NTR, has potent and long-lasting inhibition of NTR-transfected tumours in mice, and is in Phase I trial in conjunction with virally-delivered NTR enzyme. The related mustard SN 23862 has similar selectivity and superior bystander effects in animal models. Nitrobenzyl carbamates of a variety of cytotoxic amines (including aniline mustards, enediynes, duocarmycin analogues, pyrrolobenzodiazepines and the antitumour antibiotics doxorubicin, actinomycin D and mitomcyin C) are metabolised efficiently by NTR to the hydroxylamines, that fragment to release the amines. Nitroindoline derivatives of duocarmycins also show moderate selectivity for NTR-transfected cell lines in culture.
Topics: Animals; Antineoplastic Agents; Aziridines; Cell Survival; Drug Design; Genetic Therapy; Humans; Mice; Neoplasms; Nitroreductases; Prodrugs; Substrate Specificity; Tumor Cells, Cultured
PubMed: 12052212
DOI: 10.2174/1381612023394584 -
Molecular Pharmaceutics Jun 2015
Topics: Aniline Compounds; Azo Compounds; Chemistry, Pharmaceutical; Chlorambucil; Dialysis; Fluorouracil; Immune Sera; Mercaptopurine; Methotrexate; Nitrogen Mustard Compounds; Research; Tetracycline; Thiotepa; Ultraviolet Rays; Uracil Mustard; gamma-Globulins
PubMed: 26027696
DOI: 10.1021/acs.molpharmaceut.5b00302 -
Biomedicine & Pharmacotherapy =... 1983The effect of aniline mustard glucuronide (AMG), p-hydroxyaniline mustard (HAM), and aniline mustard (AM), on Walker ascites tumour cells in vitro showed that AM in... (Comparative Study)
Comparative Study
The effect of aniline mustard glucuronide (AMG), p-hydroxyaniline mustard (HAM), and aniline mustard (AM), on Walker ascites tumour cells in vitro showed that AM in about 80 times more toxic than its glucuronide but HAM is at least 800 times more toxic. A non toxic dose of AMG became completely lethal to Walker tumour cells in vitro, if bovine liver beta-glucuronidase was added to the incubation medium. Prior treatment of Walker tumour cells in vitro with glucose, increased the breakdown of AMG to HAM within the intact cells, while a non-toxic dose of the glucuronide became completely lethal to cells pretreated with glucose. The administration of AMG in combination with glucose to animals bearing the highly resistant to alkylating agents Sarcoma-180 tumour, increased the toxicity of the glucuronide but produced a slight effect on tumour growth. Glucose administration in Sarcoma-180 and ADJ/PC6 tumour bearing animals did not alter the tumour intracellular pH determined in vivo indirectly from the distribution of the weak non-metabolizable organic acid 5,5-dimethyl-2,4-oxazolinedione (DMO) between intra- and extra-cellular water. The present data suggest that the combination of aniline mustard glucuronide with glucose, could be effective in those tumours which have a high beta-glucuronidase activity and a lower tumour intracellular pH could be induced by glucose.
Topics: Aniline Mustard; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Cells, Cultured; Drug Evaluation, Preclinical; Drug Therapy, Combination; Glucose; Nitrogen Mustard Compounds; Rats; Sarcoma 180
PubMed: 6667340
DOI: No ID Found -
Spectrochimica Acta. Part A, Molecular... Dec 2017Aniline, heterocyclic aromatic amines, and arylamines are known carcinogens. Recently aniline mustard has come into prominence as a novel anticancer agent. In this...
Aniline, heterocyclic aromatic amines, and arylamines are known carcinogens. Recently aniline mustard has come into prominence as a novel anticancer agent. In this project, microwave irradiation has been used to synthesize an optically active alkylated aniline namely 2,6-dimethyl-4-(1-(p-tolyl)ethyl)aniline (abbreviated DMPA). The presence of quartet and doublet peaks in NMR and a single chromatogram in HPLC verified that the final product DMPA, prepared from the synthesis reactions, had no major impurities. By using a Lux chiral column in HPLC, two peaks have been detected in the chromatogram, which correspond to two enantiomers of the chiral aniline derivative. Fluorescence spectroscopic measurements on DMPA indicated conspicuous dependence of its emission behavior on the polarity (in terms of the empirical polarity parameter E(30)) of the homogeneous solvents used, a property important for an optical sensor. The nature of the emission profiles, along with the relevant parameter namely wavelength at emission maximum (λ) is used to infer the distribution, binding and microenvironment of the DMPA molecules in human serum albumin protein (HSA). DMPA is weakly fluorescent in aqueous buffer medium, with a dramatic enhancement in the fluorescence emission in the presence of HSA. Molecular modeling studies have been carried out on the two enantiomers (R and S) of DMPA with HSA. The implications of these findings are examined in relation to the potentialities of DMPA as a novel fluorescence sensor for biological systems.
Topics: Alkylation; Aniline Compounds; Fluorescent Dyes; Humans; Models, Molecular; Serum Albumin, Human; Spectrometry, Fluorescence; Stereoisomerism
PubMed: 28649017
DOI: 10.1016/j.saa.2017.06.008 -
Cancer Treatment Reports 1981Sprague-Dawley rats bearing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were treated with either of two aromatic alkylating agents, aniline mustard or...
Sprague-Dawley rats bearing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were treated with either of two aromatic alkylating agents, aniline mustard or melphalan, alone or combined with ovariectomy. Both drugs were applied once a week for 8 weeks. Eight-four percent of the tumors responded to ovariectomy, 38% regressing completely and 46% regressing partially. Aniline mustard, though virtually ineffective as a single agent, appeared synergistic with ovariectomy: a 100% regression rate (72% complete, 28% partial) was observed for this combination. Treatment with melphalan was as effective as ovariectomy, but the combination of melphalan with ovariectomy was no more effective than either treatment alone. The end product of aniline mustard metabolism, p-hydroxyaniline mustard O-glucuronide, may be more extensively activated by beta-glucuronidase in hormonally regressing than in growing or stationary tumors. Intratumoral levels of beta-glucoronidase occurring in DMBA-induced tumors 4 days after ovariectomy were found to be similar to those in the aniline mustard-sensitive mouse plasma cell tumor ADJ/PC6. It remains to be more extensively studied whether an effect of endocrine treatment on tumor beta-glucuronidase levels, and possibly on intracellular distribution of enzyme, could be used therapeutically. An effectively scheduled cytostatic treatment (with a drug conjugate such as that formed metabolically from aniline mustard) in conjunction with ovariectomy might be effective in the treatment of hormone-responsive breast cancer.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Aniline Mustard; Animals; Castration; Female; Glucuronidase; Mammary Neoplasms, Experimental; Melphalan; Nitrogen Mustard Compounds; Prognosis; Rats; Rats, Inbred Strains
PubMed: 6788369
DOI: No ID Found -
The Journal of Biological Chemistry Jun 1989The aziridinium of purified quinacrine mustard at 50 microM inactivates the bovine heart mitochondrial F1-ATPase with a pseudo-first order rate constant of 0.07 min-1 at...
The aziridinium of purified quinacrine mustard at 50 microM inactivates the bovine heart mitochondrial F1-ATPase with a pseudo-first order rate constant of 0.07 min-1 at pH 7.0 and 23 degrees C. An apparent Kd of 27 microM for the enzyme-reagent complex was estimated from the dependence of the rate of inactivation on the concentration of quinacrine mustard. The pH inactivation profile revealed that deprotonation of a group with a pKa of about 6.7 is necessary for inactivation. The amount of reagent incorporated into the protein increased linearly with the extent of inactivation. Complete inactivation was estimated to occur when 3 mol of reagent were incorporated/mol of F1. Enzyme, in which steady state ATPase was inactivated by 98% by quinacrine mustard, hydrolyzed substoichiometric ATP with zero order kinetics suggesting that residual activity is catalyzed by F1 in which at least one beta subunit is modified. By exploiting the reactivity of the aziridinium of covalently attached reagent with [3H] aniline, sites modified by quinacrine mustard were labeled with 3H. Isolation of radioactive cyanogen bromide peptides derived from F1 inactivated with the reagent in the presence of [3H]aniline which were identified by sequence analysis and sequence analyses of radioactive tryptic fragments arising from them have revealed the following. About two thirds of the radioactivity incorporated into the enzyme during inactivation is apparently esterified to one or more of the carboxylic acid side chains in a CNBr-tryptic fragment of the beta subunit with the sequence: 394DELSEEDK401. The remainder of the radioactivity is associated with at least two sites within the cyanogen bromide peptide containing residues 293-358 of the beta subunit. From these results it is concluded that inactivation of F1 by the aziridinium of quinacrine mustard is due, at least in part, to modification of one or more of the carboxylic acid side chains in the DELSEED segment of the beta subunit and possibly also to modification of unspecified amino acid side chains between residues 302-356 of the beta subunit.
Topics: Adenosine Triphosphate; Amino Acid Sequence; Aniline Compounds; Animals; Binding Sites; Cattle; Cyanogen Bromide; Enzyme Activation; Enzyme Stability; Hydrogen-Ion Concentration; Hydrolysis; Mitochondria, Heart; Molecular Probes; Molecular Sequence Data; Peptide Fragments; Proton-Translocating ATPases; Quinacrine; Quinacrine Mustard; Tritium
PubMed: 2524484
DOI: No ID Found -
Anti-cancer Drug Design Apr 1997Two series of analogues of the clinical antileukemic drug and DNA-intercalating ligand amsacrine have been prepared, containing aniline mustard sidechains of varying...
Two series of analogues of the clinical antileukemic drug and DNA-intercalating ligand amsacrine have been prepared, containing aniline mustard sidechains of varying reactivity, linked either at the 4-position of the intercalating acridine chromophore (type A) or at the 1'-position of the 9-anilino group (type B). DNase I footprinting assays showed that compounds of type B had stronger reversible binding to DNA than did compounds of type A. Compounds of each type showed similar patterns of alkylation-induced cleavage of DNA, and alkylate at the N7 of guanines in runs of guanines (similar to the pattern for untargeted mustards) as well as some adenines. Both classes of compounds crosslinked DNA, although those bearing relatively inactive mustards did so only at high drug/base pair ratios. However, while the patterns of DNA alkylation were broadly similar, the compounds were considerably more cytotoxic than analogous untargeted mustards. Comparison of their cytotoxicities in wild-type and DNA repair-deficient lines indicated this toxicity was due to DNA crosslinks (except for the least reactive SO2-linked mustards). The 4-linked analogues showed slightly higher in vivo antileukemic activity than the corresponding 1'-linked analogues.
Topics: Amsacrine; Aniline Mustard; Animals; CHO Cells; Cricetinae; DNA, Recombinant; Intercalating Agents; Leukemia, Experimental; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Tumor Cells, Cultured
PubMed: 9154110
DOI: No ID Found -
Journal of Medicinal Chemistry Apr 1990A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with...
A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with that of the corresponding simple aniline mustards. The alkylating groups were anchored to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain of fixed length attached at the mustard 4-position through a link group X, while the corresponding simple mustards possessed an electronically identical small group at this position. The link group was varied to provide a series of compounds of similar geometry but widely differing mustard reactivity. Variation in biological activity should then largely be a consequence of this varying reactivity. Rates of mustard hydrolysis in the two series related only to the electronic properties of the link group, with attachment of the intercalating chromophore having no effect. The cytotoxicities of the simple mustards correlated well with group electronic properties (with a 200-300-fold range in IC50S). The corresponding DNA-targeted mustards were much more potent (up to 100-fold), but their IC50 values varied much less with linker group electronic properties. Most of the DNA-targeted mustards showed in vivo antitumor activity, being both more active and more dose-potent than either the corresponding untargeted mustards and chlorambucil. These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.
Topics: Alkylating Agents; Alkylation; Aniline Mustard; Animals; Antineoplastic Agents; Cell Line; Chemical Phenomena; Chemistry; DNA, Neoplasm; Kinetics; Leukemia, Experimental; Mice; Nitrogen Mustard Compounds; Structure-Activity Relationship
PubMed: 2319563
DOI: 10.1021/jm00166a015