-
Frontiers in Bioscience : a Journal and... Nov 2000Aziridinyl quinones can be activated by cellular reductases eg. DT-diaphorase and cytochrome P450 reductase to form highly reactive DNA alkylating agents. The mechanisms... (Review)
Review
Aziridinyl quinones can be activated by cellular reductases eg. DT-diaphorase and cytochrome P450 reductase to form highly reactive DNA alkylating agents. The mechanisms by which this activation and alkylation take place are many and varied. Using clinically relevant and experimental agents this review will describe many of these mechanisms. The agents discussed are Mitomycin C, EO9 and analogues, diaziridinylbenzoquinones and the pyrrolo[1, 2-alpha]benzimidazolequinones.
Topics: Alkylation; Antineoplastic Agents, Alkylating; Aziridines; Benzimidazoles; Benzoquinones; Carbazilquinone; DNA; Doxorubicin; Humans; Indolequinones; Indoles; Mitomycin; Molecular Structure; Oxidation-Reduction; Quinones; Structure-Activity Relationship
PubMed: 11056081
DOI: 10.2741/hargreav -
Drug Metabolism and Disposition: the... May 2019Duocarmycins [including cyclopropyl pyrroloindole (CPI) or cyclopropyl benzoindole (CBI)] are a class of DNA minor-groove alkylators and seco-CPI/CBIs are synthetic...
Duocarmycins [including cyclopropyl pyrroloindole (CPI) or cyclopropyl benzoindole (CBI)] are a class of DNA minor-groove alkylators and seco-CPI/CBIs are synthetic pro-forms that can spirocyclize to CPI/CBI. Bis-CPI/CBIs are potential drug candidates because of their enhanced cytotoxicity from DNA crosslinking, but it is difficult to analyze them for structure-activity correlation because of their DNA reactivity. To study their DNA alkylation, neutral thermal hydrolysis has been frequently applied to process depurination. However, unwanted side reactions under this condition have been reported, which could lead to poor correlation of DNA alkylation data with efficacy results, especially for bis-CPI/CBIs. In this study, an acidic depurination method was developed and applied for analysis of DNA alkylation and shown to be an easier and milder method than the traditional neutral thermal hydrolysis. DNA alkylation and stability of three bis-seco-CBIs were characterized in comparison with two mono-seco-CPIs. The results suggested that: 1) The acidic depurination method was capable of capturing a more representative population, sometimes a different population, of DNA adducts as they existed on DNA compared with the heat depurination method. 2) Di-adenine adducts were captured as expected for the CBI dimers, although the major type of adduct was still mono-adenine adducts. 3) The rate of DNA alkylation, DNA adduct profile, and relative amounts of di-adduct versus mono-adduct were significantly affected by the size, and possibly lipophilicity, of the nonalkylating part of the molecules. 4) Spirocyclization and amide hydrolysis represented two major pathways of degradation. Overall, by applying acidic depurination analyses, this study has illustrated DNA adduct characteristics of novel bis-seco-CBIs with dominating mono-alkylation and provides an alternative method for evaluating DNA minor-groove alkylators. These findings provide an effective analytical tool to evaluate DNA alkylators and to study the DNA alkylation that is a disposition mechanism of these compounds.
Topics: Adenine; Alkylating Agents; Alkylation; Antineoplastic Agents, Alkylating; DNA; DNA Adducts; Duocarmycins
PubMed: 30858239
DOI: 10.1124/dmd.118.085209 -
Biochimie Sep 1985Carcinogenic alkylating agents, including nitrosamines, are able to alkylate DNA at various sites. This review presents evidence of the high degree of specificity in the... (Review)
Review
Carcinogenic alkylating agents, including nitrosamines, are able to alkylate DNA at various sites. This review presents evidence of the high degree of specificity in the type of DNA damage induced by various N-nitroso compounds and in the DNA repair processes among tissues or cells of different species. The O6-alkylguanine DNA alkyltransferase activity in various human and rodent tissues is discussed as well as the detection of O6-methylguanine in human DNA, using monoclonal antibodies and radioimmunoassay. The relevance of these findings to the mechanisms of cancer induction by nitrosamines is discussed.
Topics: Alkylating Agents; Alkylation; Animals; Carcinogens; Cricetinae; DNA; DNA Repair; Humans; Liver; Liver Neoplasms, Experimental; Methylation; Methyltransferases; O(6)-Methylguanine-DNA Methyltransferase; Rats
PubMed: 3910113
DOI: 10.1016/s0300-9084(85)80288-1 -
Nature Chemical Biology Feb 2006(+)-Yatakemycin (1, Fig. 1) and (+)-duocarmycin SA (2) are exceptionally potent, naturally occurring antitumor agents that derive their biological properties through a...
(+)-Yatakemycin (1, Fig. 1) and (+)-duocarmycin SA (2) are exceptionally potent, naturally occurring antitumor agents that derive their biological properties through a characteristic sequence-selective DNA-alkylation reaction. Studies have shown that both the AT-rich binding selectivity (shape-selective recognition) and the alkylation catalysis (shape-dependent catalysis) that contribute to the alkylation selectivity are dependent on the DNA minor groove shape and size characteristics of an AT-rich sequence (ref. 6 and references therein; refs. 7,8). Here we report the alkylation properties of yatakemycin and duocarmycin SA on free DNA (alpha-satellite DNA) and the same sequence bound in a nucleosome core particle (NCP) modeling the state of DNA in eukaryotic cells. Both compounds showed a clear, relatively unaltered ability to alkylate DNA packaged in NCPs in terms of both alkylating efficiency and sequence selectivity, despite the steric and conformational perturbations imposed by NCP packaging. These findings highlight the dynamic nature of NCP-bound DNA and illustrate that cell- and protein-free DNA-alkylation studies of members of this class of antitumor drugs provide valuable insights into their properties.
Topics: Antineoplastic Agents, Alkylating; DNA; Duocarmycins; Indoles; Nucleosomes; Pyrroles
PubMed: 16415862
DOI: 10.1038/nchembio761 -
Analytical Chemistry Jan 2018
Review
Topics: Alkylating Agents; Amines; Animals; Chemistry Techniques, Analytical; DNA; DNA Adducts; DNA Damage; Heterocyclic Compounds; Humans; Reactive Oxygen Species
PubMed: 29084424
DOI: 10.1021/acs.analchem.7b04247 -
Biochemistry Dec 2000Azinomycin B (also known as carzinophilin A) contains two electrophilic functional groups-an epoxide and an aziridine residue-that react with nucleophilic sites in...
Azinomycin B (also known as carzinophilin A) contains two electrophilic functional groups-an epoxide and an aziridine residue-that react with nucleophilic sites in duplex DNA to form cross-links at 5'-dGNT and 5'-dGNC sequences. Although the aziridine residue of azinomycin is undoubtedly required for cross-link formation, analogues containing an intact epoxide group but no aziridine residue retain significant biological activity. Azinomycin epoxide analogues (e.g., 5 and 6) are of interest due to their potent biological activity and because there is evidence that azinomycin may decompose in vivo to yield such compounds. To investigate the chemical events underlying the toxicity of azinomycin epoxides, DNA binding and alkylation by synthetic analogues of azinomycin B (6, 8, and 9) that comprise the naphthalene-containing "left half" of the antibiotic have been investigated. The epoxide-containing analogue of azinomycin (6) efficiently alkylates guanosine residues in duplex DNA. DNA alkylation by 6 is facilitated by noncovalent binding of the compound to the double helix. The results of UV-vis absorbance, fluorescence spectroscopy, DNA winding, viscometry, and equilibrium dialysis experiments indicate that the naphthalene group of azinomycin binds to DNA via intercalation. Equilibrium dialysis experiments provide an estimated binding constant of (1.3 +/- 0.3) x 10(3) M(-)(1) for the association of a nonalkylating azinomycin analogue (9) with duplex DNA. The DNA-binding and alkylating properties of the azinomycin epoxide 6 provide a basis for understanding the cytotoxicity of azinomycin analogues which contain an epoxide residue but no aziridine group and may provide insight into the mechanisms by which azinomycin forms interstrand DNA cross-links.
Topics: Alkylation; Anti-Bacterial Agents; Antineoplastic Agents, Alkylating; Cross-Linking Reagents; DNA; Daunorubicin; Epoxy Compounds; Glycopeptides; Intercellular Signaling Peptides and Proteins; Naphthalenes; Nucleic Acid Conformation; Peptides; Spectrometry, Fluorescence
PubMed: 11101313
DOI: 10.1021/bi001998d -
Chemical Research in Toxicology Nov 2006Alkylating agents, including environmental and endogenous carcinogens and DNA targeting antineoplastic agents, that adduct DNA via intermediates with significant... (Review)
Review
Alkylating agents, including environmental and endogenous carcinogens and DNA targeting antineoplastic agents, that adduct DNA via intermediates with significant cationic charge show a sequence selectively in their covalent bonding to nucleobases. The resulting patterns of alkylation eventually contribute to the agent-dependent distributions and types of mutations. The origin of the regioselective modification of DNA by electrophiles has been attributed to steric and/or electronic factors, but attempts to mechanistically model and predict alkylation patterns have had limited success. In this review, we present data consistent with the role of the intrinsic sequence-dependent electrostatic landscape (SDEL) in DNA that modulates the equilibrium binding of cations and the bonding of reactive charged alkylating agents to atoms that line the floor of the major groove of DNA.
Topics: Alkylating Agents; Base Sequence; Cations; Crystallography, X-Ray; DNA; Models, Molecular; Molecular Sequence Data; Nucleic Acid Conformation; Static Electricity
PubMed: 17112226
DOI: 10.1021/tx060127n -
Frontiers in Bioscience (Landmark... Sep 2023O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair enzyme, which reverses the alkylation of guanine O6 through directtransfer of the methyl group, maintains... (Review)
Review
O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair enzyme, which reverses the alkylation of guanine O6 through directtransfer of the methyl group, maintains the gene stability and avoids tumor occurrence. Studies have shown that gene methylation, polymorphism and protein expression are involved in the process of various tumor development, such as colon cancer, gastric carcinoma, etc. gene promotes methylation, protein expression and enzyme activity from various tissues, which resultsin different effects on the prognosis of patients. MGMT promoter methylation is a positive factor for the prognosis of Glioblastoma (GBM), which can prolong overall survival and progression-free survival, reduce the resistance of tumor cells to temozolomide treatment, and improve the prognosis. The treatment of tumors based on MGMT focuses on three aspects: targeting MGMT to increase the sensitivity of alkylated drug therapy in tumors, immunotherapy combined with alkylated agents on tumor treatment, and treatment for patients with MGMT promoter non-methylation. Similarly, a number of studies have targeted MGMT to reduce alkylated agent resistance in other systems. Although numerous studies on MGMT in tumors have been reported, there are problems that need to be solved, such as selection and consensus of MGMT promoter methylation detection methods (CpG detection sites, cut-off value) and the treatment of MGMT non-methylated GBM patients, especially elderly patients. In this review, we describe the regulation of MGMT expression and its role inchemotherapy, especially in gliomas. Further studies exploring new methods targeting MGMT with better curative effect and less toxicity are advocated. We anticipate that these developments will be progressive and sufficiently used for clinical application.
Topics: Humans; Antineoplastic Agents, Alkylating; Brain Neoplasms; Dacarbazine; DNA; DNA Methylation; DNA Repair Enzymes; Glioblastoma; O(6)-Methylguanine-DNA Methyltransferase
PubMed: 37796680
DOI: 10.31083/j.fbl2809197 -
Nucleic Acids Research May 2023The importance of non-canonical DNA structures such as G-quadruplexes (G4) and intercalating-motifs (iMs) in the fine regulation of a variety of cellular processes has...
The importance of non-canonical DNA structures such as G-quadruplexes (G4) and intercalating-motifs (iMs) in the fine regulation of a variety of cellular processes has been recently demonstrated. As the crucial roles of these structures are being unravelled, it is becoming more and more important to develop tools that allow targeting these structures with the highest possible specificity. While targeting methodologies have been reported for G4s, this is not the case for iMs, as evidenced by the limited number of specific ligands able to bind the latter and the total absence of selective alkylating agents for their covalent targeting. Furthermore, strategies for the sequence-specific covalent targeting of G4s and iMs have not been reported thus far. Herein, we describe a simple methodology to achieve sequence-specific covalent targeting of G4 and iM DNA structures based on the combination of (i) a peptide nucleic acid (PNA) recognizing a specific sequence of interest, (ii) a pro-reactive moiety enabling a controlled alkylation reaction, and (iii) a G4 or iM ligand orienting the alkylating warhead to the reactive residues. This multi-component system allows for the targeting of specific G4 or iM sequences of interest in the presence of competing DNA sequences and under biologically relevant conditions.
Topics: Alkylating Agents; Alkylation; DNA; G-Quadruplexes; Ligands; Light; Color
PubMed: 36971129
DOI: 10.1093/nar/gkad189 -
Critical Reviews in Biochemistry and... Apr 2021DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are... (Review)
Review
DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are deeply entwined with the development of poisonous materials originally intended for use in warfare. Over the last decades, their anti-proliferative effects have focused on the specific mechanisms by which they damage DNA, and the factors involved in the repair of such damage. Due to the variety of aberrant adducts created even for the simplest alkylating agents, numerous pathways of repair are engaged as a defense against this damage. More recent work has underscored the role of RNA damage in the cellular response to these agents, although the understanding of their role in relation to established DNA repair pathways is still in its infancy. In this review, we discuss the chemistry of alkylating agents, the numerous ways in which they damage nucleic acids, as well as the specific DNA and RNA repair pathways which are engaged to counter their effects.
Topics: Alkylating Agents; Alkylation; Animals; DNA; DNA Damage; DNA Repair; Humans; RNA
PubMed: 33430640
DOI: 10.1080/10409238.2020.1869173