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Nucleosides & Nucleotides 1999A new class of sequence-specific DNA alkylating agents were developed based on the reactivity of duocarmycin A and the DNA-reading ability of pyrrole-imidazole...
A new class of sequence-specific DNA alkylating agents were developed based on the reactivity of duocarmycin A and the DNA-reading ability of pyrrole-imidazole polyamide. The DNA alkylation sequence specificity by duocarmycin A can be modulated by a variety of pyrrole-imidazole triamides in a predictable manner. Novel hybrids of the segment A of duocarmycin A and pyrrole-imidazole polyamides efficiently and highly selectively alkylated the target base possessing match sequences of Dervan's binding code.
Topics: Alkylating Agents; Alkylation; DNA; Duocarmycins; Indoles; Nylons; Pyrrolidinones
PubMed: 10474238
DOI: 10.1080/07328319908044799 -
Current Topics in Medicinal Chemistry 2004Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently... (Review)
Review
Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researcher's attention not only for their biological activity, but also for its non intercalative binding to the minor groove of double-stranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicles for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself. In the last few years, several hybrid compounds, in which known antitumor derivatives or simple active moieties of known antitumor agents have been tethered to distamycin frames, have been designed, synthesized and tested. Several efforts have been made to modify DNA sequence selectivity and stability of the distamycin and the structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles obtaining a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety, by means of the substitution with various groups, which includes ionizable, acid or basic, and non-ionizable groups, has been also studied. The synthesis of a hybrid deriving among the combination of the distamycin A and naturally occurring alkylating agent has been also reported. Several classes of distamycin derivatives that have been reported in the published literature have been described in this review article.
Topics: Alkylating Agents; Antineoplastic Agents; DNA; Distamycins; Humans; Mustard Compounds; Nucleic Acid Conformation
PubMed: 14754456
DOI: 10.2174/1568026043451474 -
Cancer Research Apr 1986The DNA sequence selectivities of guanine-N7 alkylation produced by three chloroethylating antitumor agents, 1-(2-chloroethyl)-3-(cis-2-hydroxy) cyclohexyl-1-nitrosourea...
The DNA sequence selectivities of guanine-N7 alkylation produced by three chloroethylating antitumor agents, 1-(2-chloroethyl)-3-(cis-2-hydroxy) cyclohexyl-1-nitrosourea (cis-2-OH CCNU), 2-chloroethyl (methylsulfonyl)methanesulfonate, and 8-carbamoyl-3-(2-chloroethyl)imidazo-[5,1-d]-1,2,3,5-tetrazin-4(3H )-one (mitozolomide), were examined using a modification of the Maxam and Gilbert sequencing technique. In a region of pBR322 DNA, 2-chloroethyl (methylsulfonyl)methanesulfonate produced approximately the same degree of alkylation at all guanines. cis-2-OH CCNU, however, preferentially alkylated the middle guanines in runs of three or more guanines; the intensity of the reaction increased with the number of adjacent guanines in the DNA sequence. Mitozolomide produced the same pattern of preferential alkylation but not as intensely as cis-2-OH CCNU. Three other nitrosoureas, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1-(2-fluorethyl)-3-cyclohexyl-1-nitrosourea, and 1-(2-chloroethyl)-1-nitrosourea gave similar patterns of alkylation to that of cis-2-OH CCNU at pH 7.2. The ratio of 7-hydroxyethylguanine to 7-chloroethylguanine was approximately the same following treatment of the synthetic polymers dGn X dCn and (dG X dC)n with cis-2-OH CCNU, indicating that 7-chloroethylation and 7-hydroxyethylation were enhanced similarly by the presence of adjacent guanines. Ethylnitrosourea produced relatively little alkylation preference. The results suggest that the alkylating intermediates, 2-chloroethyldiazohydroxide and 2-hydroxyethyldiazohydroxide, tend to react preferentially with those guanine-N7 positions the electronegativity of which is enhanced by the presence of neighboring guanines. This is consistent with the presence of cationic character in the alkylating centers of these intermediates. 2-Chloroethyl (methylsulfonyl)methanesulfonate and ethyldiazohydroxide would not be expected to have strong cationic character, in agreement with their lack of sequence selectivity.
Topics: Alkylating Agents; Alkylation; Antineoplastic Agents; Autoradiography; Base Sequence; DNA; Ethylnitrosourea; Guanine; Hydrogen-Ion Concentration; Lomustine; Mesylates; Nitrogen Mustard Compounds
PubMed: 3004713
DOI: No ID Found -
Current Medicinal Chemistry 2005It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action.... (Review)
Review
It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalating or alkylating activity are described and evaluated for prospective applications. Furthermore there exists DNA minor groove binder with different basic structures which does not possess the typical polyamide chain, including dimeric intercalating chromophores. Finally new results about peptide nucleic acids and related nucleic acid bases linked with polyamides are reported. In pronounced examples the structural chemistry, synthesis, DNA binding with several biophysical methods, molecular aspects, structure activity relationship, topoisomerase inhibition, antitumour and antibacterial effects are discussed in detail.
Topics: Alkylating Agents; Binding Sites; DNA; Drug Design; Intercalating Agents; Ligands; Models, Molecular; Molecular Structure; Nucleic Acid Conformation
PubMed: 16305474
DOI: 10.2174/092986705774454698 -
Chemical Research in Toxicology Jan 2001The bifunctional alkylating agent, melphalan, forms adducts on DNA that are recognized by two previously described monoclonal antibodies, MP5/73 and Amp4/42.... (Comparative Study)
Comparative Study
The bifunctional alkylating agent, melphalan, forms adducts on DNA that are recognized by two previously described monoclonal antibodies, MP5/73 and Amp4/42. Immunoreactivity to MP5/73 was lost when alkylated DNA was exposed to alkaline pH, while Amp4/42 only recognized the structures formed after the alkali treatment. Competitive enzyme-linked immunoadsorbent assays (ELISAs) indicated that in 0.01 and 0.1 M NaOH, loss of immunoreactivity to MP5/73 occurred with half-lives that were at least 2-fold longer than half-lives for gain of immunoreactivity to Amp4/42. This supported previously published evidence that Amp4/42 did not simply recognize all the products formed by alkali treatment of adducts that were initially recognized by MP5/73. Adducts recognized by MP5/73 on RNA were considerably more stable at 100 degrees C and pH 7 than adducts on DNA. This was consistent with the hypothesis that immunorecognition involved N7 guanine adducts and ruled out the involvement of phosphotriesters in immunoreactivity. Synthetic oligodeoxyribonucleotides, covalently immobilized onto 96-well plates, were reacted with melphalan and incubated for various periods with alkali, and then the levels of adducts recognized by each antibody in replicate wells were assayed by a direct binding ELISA. Adducts formed on oligodeoxyguanylic acid were recognized very weakly by Amp4/42, unlike other DNA sequences that were tested. Retention of immobilized DNA during alkali treatment was confirmed by immunoassay of cisplatin adducts. Poor recognition by Amp4/42 of adducts in oligodeoxyguanylic acid was confirmed by a competitive ELISA. Amp4/42, unlike MP5/73, efficiently recognized adducts resulting from alkylation of DNA with chlorambucil. It is concluded that the two antibodies recognized melphalan adducts in different DNA sequence environments and that this explains (a) the different alkali stability of immunoreactive adducts and (b) previous results which showed that, in DNA from melphalan-treated cells, adducts recognized by Amp4/42 formed a smaller proportion of total adducts compared to DNA alkylated in vitro. The results presented here indicate that this was caused by a marked cellular influence on the overall sequence-dependent pattern of DNA alkylation or repair.
Topics: Alkylation; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Base Sequence; Cattle; Chlorambucil; Cross-Linking Reagents; DNA; DNA Adducts; Drug Stability; Enzyme-Linked Immunosorbent Assay; Hot Temperature; Hydrogen-Ion Concentration; Kinetics; Melphalan; Molecular Sequence Data
PubMed: 11170510
DOI: 10.1021/tx000178z -
Journal of the American Chemical Society Feb 2007Acylfulvenes (AFs) are a class of semisynthetic agents with high toxicity toward certain tumor cells, and for one analogue, hydroxymethylacylfulvene (HMAF), clinical...
Acylfulvenes (AFs) are a class of semisynthetic agents with high toxicity toward certain tumor cells, and for one analogue, hydroxymethylacylfulvene (HMAF), clinical trials are in progress. DNA alkylation by AFs, mediated by bioreductive activation, is believed to contribute to cytotoxicity, but the structures and chemical properties of corresponding DNA adducts are unknown. This study provides the first structural characterization of AF-specific DNA adducts. In the presence of a reductive enzyme, alkenal/one oxidoreductase (AOR), AF selectively alkylates dAdo and dGuo in reactions with a monomeric nucleoside, as well as in reactions with naked or cellular DNA, with 3-alkyl-dAdo as the apparently most abundant AF-DNA adduct. Characterization of this adduct was facilitated by independent chemical synthesis of the corresponding 3-alkyl-Ade adduct. In addition, in naked or cellular DNA, evidence was obtained for the formation of an additional type of adduct resulting from direct conjugate addition of Ade to AF followed by hydrolytic cyclopropane ring-opening, indicating the potential for a competing reaction pathway involving direct DNA alkylation. The major AF-dAdo and AF-dGuo adducts are unstable under physiologically relevant conditions and depurinate to release an alkylated nucleobase in a process that has a half-life of 8.5 h for 3-alkyladenine and less than approximately 2 h for dGuo adducts. DNA alkylation further leads to single-stranded DNA cleavage, occurring exclusively at dGuo and dAdo sites, in a nonsequence-specific manner. In AF-treated cells that were transfected with either AOR or control vectors, the DNA adducts identified match those from in vitro studies. Moreover, a positive correlation was observed between DNA adduct levels and cell sensitivity to AF. The potential contributing roles of AOR-mediated bioactivation and adduct stability to the cytotoxicity of AF are discussed.
Topics: Alcohol Oxidoreductases; Alkylation; Animals; Antineoplastic Agents, Alkylating; Cattle; Cells, Cultured; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Deoxyadenosines; Deoxyguanosine; Humans; NADP; Nucleic Acid Conformation; Sesquiterpenes; Spectrometry, Mass, Electrospray Ionization; Spiro Compounds
PubMed: 17256933
DOI: 10.1021/ja0665951 -
ChemMedChem Sep 2014Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of...
Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.
Topics: Alkylating Agents; Alkylation; Antineoplastic Agents, Alkylating; Cyclization; DNA Cleavage; Molecular Conformation; Nitrogen Mustard Compounds; Piperazines; Piperidines; Plasmids
PubMed: 24616300
DOI: 10.1002/cmdc.201400034 -
ChemistryOpen Jun 2024In previous works, we demonstrated that tertiary 3-chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions....
In previous works, we demonstrated that tertiary 3-chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3-chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N-chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3-chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3-chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart.
Topics: Piperidines; Antineoplastic Agents, Alkylating; Alkylating Agents; DNA Cleavage; Humans; Aziridines; DNA; Succinimides
PubMed: 38088585
DOI: 10.1002/open.202300181 -
Mutation Research Sep 2002Alkylating agents are environmental genotoxic agents with mutagenic and carcinogenic potential, however, their properties are also exploited in the treatment of... (Comparative Study)
Comparative Study Review
Alkylating agents are environmental genotoxic agents with mutagenic and carcinogenic potential, however, their properties are also exploited in the treatment of malignant diseases. O(6)-Methylguanine is an important adduct formed by methylating agents that, if not repaired, can lead to mutations and death. Its repair is carried out by O(6)-methylguanine DNA-methyltransferase (MTase) in an unique reaction in which methyl groups are transferred to the cysteine acceptor site of the protein itself. Exposure of Escherichia coli cells to sublethal concentrations of methylating agents triggers the expression of a set of genes, which allows the cells to tolerate DNA lesions, and this kind of inducible repair is called the adaptive response. The MTase of E. coli, encoded by the ada gene was the first MTase to be discovered and one of best characterised. Its repair and regulatory mechanisms are understood in considerable detail and this bacterial protein played a key role in identification of its counterparts in other living organisms. This review summarises the nature of alkylation damage in DNA and our current knowledge about the adaptive response in E. coli. I also include a brief mention of MTases from other organisms with the emphasis on the human MTase, which could play a crucial role in both cancer prevention and cancer treatment.
Topics: Adaptation, Physiological; Alkylating Agents; Alkylation; Animals; Antineoplastic Agents, Alkylating; Bacterial Proteins; DNA Damage; DNA, Bacterial; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Humans; Mammals; Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Prokaryotic Cells; SOS Response, Genetics; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors
PubMed: 12220590
DOI: 10.1016/s1383-5742(02)00025-x -
Nucleic Acids Research Dec 1998Monocrotaline is a pyrrolizidine alkaloid known to cause toxicity in humans and animals. Its mechanism of biological action is still unclear although DNA crosslinking...
Monocrotaline is a pyrrolizidine alkaloid known to cause toxicity in humans and animals. Its mechanism of biological action is still unclear although DNA crosslinking has been suggested to a play a role in its activity. In this study we found that an active metabolite of monocrotaline, dehydromonocrotaline (DHM), alkylates guanines at the N7 position of DNA with a preference for 5'-GG and 5'-GA sequences. In addition, it generates piperidine- and heat-resistant multiple DNA crosslinks, as confirmed by electrophoresis and electron microscopy. On the basis of these findings, we propose that DHM undergoes rapid polymerization to a structure which is able to crosslink several fragments of DNA.
Topics: Alkylating Agents; Alkylation; Animals; Cross-Linking Reagents; DNA Adducts; DNA Footprinting; DNA Fragmentation; Guanine; Hot Temperature; Humans; Models, Chemical; Monocrotaline; Mutagenesis; Plasmids
PubMed: 9826770
DOI: 10.1093/nar/26.23.5441