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Current Medicinal Chemistry Apr 2001Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards,... (Review)
Review
Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards, where attachment of the mustard unit to carrier molecules can change the normal patterns of both regio- and sequence-selectivity, from reaction primarily at most guanine N7 sites in the major groove to a few adenine N3 sites at the 3'-end of poly(A/T) sequences in the minor groove. Carrier molecules discussed for mustards are intercalators, polypyrroles, polyimidazoles, bis(benzimidazoles), polybenzamides and anilinoquinolinium salts. In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect of their patterns of alkylation (at the 2-amino group of guanine). Recent work on the pyrrolobenzodiazepine and cyclopropaindolone classes of natural product minor groove binders is also reviewed.
Topics: Alkylating Agents; Animals; Anthramycin; Antibiotics, Antineoplastic; Benzofurans; Bisbenzimidazole; Chlorambucil; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA; Distamycins; Duocarmycins; Humans; Indoles; Netropsin; Nitrogen Mustard Compounds; Pyrroles; Structure-Activity Relationship
PubMed: 11281840
DOI: 10.2174/0929867003373283 -
Biochemistry Oct 1996Ecteinascidin 743 is one of several related marine alkaloids isolated from the Caribbean tunicate Ecteinascidia turbinata. It is remarkably active and potent in a... (Comparative Study)
Comparative Study
DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata.
Ecteinascidin 743 is one of several related marine alkaloids isolated from the Caribbean tunicate Ecteinascidia turbinata. It is remarkably active and potent in a variety of in vitro and in vivo systems and has been selected for development as an anticancer agent. The present study investigates the interactions of ecteinascidin 743 with DNA. Ecteinascidin 743 retarded the electrophoretic migration of both supercoiled and relaxed simian virus 40 DNA even in the presence of sodium dodecyl sulfate and after ethanol precipitation, consistent with covalent DNA modifications. Similar results were obtained in a DNA oligonucleotide derived from ribosomal DNA. However, DNA denaturation reversed the DNA modifications. The homopolymeric oligonucleotide dG/dC was modified while neither the dI/dC nor the dA/dT oligonucleotides were, consistent with covalent attachment of ecteinascidin 743 to the exocyclic amino group at position 2 of guanine. Ecteinascidin 743 was then compared to another known DNA minor groove alkylating agent, anthramycin, which has also been shown to alkylate guanine N2. Footprinting analyses with DNase I and 1,10-phenanthroline-copper and exonuclease III digestions showed that ecteinascidin 743 covers three to five bases of DNA and exhibits a different sequence specificity than anthramycin in the Escherichia coli tyrosine tRNA promoter (tyrT DNA). The binding of ecteinascidin to DNA was abolished when guanines were substituted with inosines in this promoter. A band shift assay was designed to evaluate the influence of the bases flanking a centrally located guanine in an oligonucleotide containing inosines in place of guanines elsewhere. Ecteinascidin 743 and anthramycin showed similarities as well as differences in sequence selectivity. Ecteinascidin 743-guanine adducts appeared to require at least one flanking guanine and were strongest when the flanking guanine was 3' to the targeted guanine. These data indicate that ecteinascidin 743 is a novel DNA minor groove, guanine-specific alkylating agent.
Topics: Alkylation; Animals; Anthramycin; Antineoplastic Agents, Alkylating; Base Sequence; Binding Sites; DNA; DNA Footprinting; Dioxoles; Guanine; Isoquinolines; Molecular Sequence Data; Molecular Structure; Tetrahydroisoquinolines; Trabectedin; Urochordata
PubMed: 8873596
DOI: 10.1021/bi960306b -
Anti-cancer Drug Design Sep 1995Two groups of isomeric N1-alkoxyalkyl-bis-benzimidazoles differing in the orientation of the N-alkoxyalkyl group (R) with respect to the DNA minor groove have been...
Two groups of isomeric N1-alkoxyalkyl-bis-benzimidazoles differing in the orientation of the N-alkoxyalkyl group (R) with respect to the DNA minor groove have been examined as to their reaction with DNA. Agarose gel mobility shift assay demonstrates that the 'R-inward' isomers alkylate and cause thermally induced strand breakage, in contrast to a much weaker reaction of the 'R-outward' isomers. Complementary studies using high-resolution polyacrylamide gel electrophoresis confirmed relatively weak but definite alkylation-induced thermal cleavage at all available G base sites, but at selected A sites. The alkylation reaction is interpreted in terms of an SN2 displacement of the alkoxy group by nucleophiles within the groove, in contrast to the complete lack of such nucleophilic displacement of these drugs in bulk solution. Reaction with all available Gs is interpreted in terms of nucleophilic strength within the DNA minor groove whereas, in contrast, reaction at the A residues appears to be determined primarily by initial molecular recognition of a DNA site by the drug, followed by an SN2 displacement. The relative cytotoxic potencies of these drugs against KB human tumor cells may be explained on the basis of this mechanism.
Topics: Alkylation; Antineoplastic Agents, Alkylating; Base Sequence; Benzimidazoles; Bisbenzimidazole; DNA; DNA Adducts; Humans; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 7575987
DOI: No ID Found -
Chemical Research in Toxicology Mar 2006DNA phosphate oxygens are sites for alkylation leading to DNA phosphotriester adduct (PTE) formation. Previously, we have reported that the manifestation of PTEs was...
Phosphate alkylation in different DNA substrates: the role of local DNA sequence and electrophile character in determining the nonrandom nature of phosphotriester adduct formation.
DNA phosphate oxygens are sites for alkylation leading to DNA phosphotriester adduct (PTE) formation. Previously, we have reported that the manifestation of PTEs was nonrandom in mouse liver DNA treated in vivo [Guichard et al. (2000) Cancer Res. 60, 1276-1282], and while further studies revealed possible PTE repair, this was determined not to play a role in the observed nonrandom manifestation in vivo [Le Pla et al. (2004) Chem. Res. Toxicol. 17, 1491-1500]. In the present study, to determine whether the nonrandom manifestation of PTEs in vivo was specifically due to their nonrandom formation, we have compared the in vitro formation of diethylsulfate (DES)-induced PTEs in h2E1/OR human B-lymphoblastoid cells, their isolated nuclei, and their isolated DNA, using the 5' nearest neighbor analysis postlabeling procedure developed by Le Pla et al.. Furthermore, to determine the role of electrophile character in PTE manifestation, prepared oligonucleotides ([dT](20)[dG](20):[dC](20)[dA](20)) were treated with three alkylating agents of differing electrophilic character (DES, methylnitrosourea, and ethylnitrosourea), and PTE manifestation was assessed by postlabeling. The formation of PTEs was determined to be nonrandom in the whole cells, nuclei, and DNA, with PTEs being formed to a greater extent 3' to pyrimidine moieties than 3' to purine moieties. The studies with the oligonucleotides confirm these observations and demonstrate that the nonrandom formation of PTEs is primarily determined by DNA sequence, and not by DNA packaging/chromatin factors, and that the extent of the nonrandom formation of PTEs is also governed by electrophile reactivity, with the more reactive electrophiles yielding a more random formation of PTEs. From our observations, we propose a model for the nonrandom formation of PTEs, which is governed by (i) the phosphate oxygens having to compete with adjacent nucleophilic sites for the alkylating electrophile and (ii) the electrophile's inherent reactivity.
Topics: Alkylating Agents; Alkylation; Autoradiography; Buffers; Cell Line; Culture Media; DNA; Electrophoresis, Polyacrylamide Gel; Ethylnitrosourea; Humans; Methylnitrosourea; Oligonucleotides; Oxygen; Phosphates; Sulfuric Acid Esters
PubMed: 16544945
DOI: 10.1021/tx050298c -
Developments in Toxicology and... 1983Alkylating agents have proved useful as models, especially for low molecular weight mutagens and carcinogens, to probe molecular mechanisms of genotoxicity. Results of...
Alkylating agents have proved useful as models, especially for low molecular weight mutagens and carcinogens, to probe molecular mechanisms of genotoxicity. Results of many studies have indicated that not all DNA substitutions cause mutagenic or carcinogenic responses. Often, quantitatively minor alkylation products are responsible for initiating these biological processes. The factors that influence the distribution of DNA substitution products include: the SN1 reactivity of the electrophilic species; the nucleophilicity and steric accessability of the DNA site; van der Waals or electrostatic interactions that attract the agent to specific DNA sites; and post-alkylation rearrangements. With low molecular weight alkylating agents, a primary determinant of product distribution in DNA, and of genotoxic potential, is the electrophilic reactivity. Agents with high SN1 reactivity (low Swain -Scott s factors) generally have high mutagenic and carcinogenic activity, at equal levels of total DNA alkylkation . This appears to be due to the ability of such agents to cause relatively more alkylation at oxygen sites in DNA, especially at O6 of guanine and at O4 of thymine. Alkylation of DNA alone is insufficient to induce cancer or mutations. Post-alkylation factors such as DNA repair, rate of cell turnover, or presence of tumor promoters can have a profound effect on the biological response to DNA damage (1,5,6,24,42). In this sense, the persistence of a specific miscoding of altered DNA base is significant in carcinogenesis or mutagenesis only to the extent that it remains in DNA long enough to be fixed into the code. This concept necessarily assumes that the altered base has promutagenic potential. Persistence of an alkylated DNA constituent does not, by itself, indicate that the alkylated constituent has biological significance.
Topics: Alkylating Agents; Alkylation; Animals; DNA; DNA Replication; Humans; Mutagens; Mutation; Neoplasms; Phosphates; Purines; Pyrimidines
PubMed: 6677460
DOI: No ID Found -
Contributions To Gynecology and... 1991
Review
Topics: Alkylating Agents; Cell Transformation, Neoplastic; DNA; Humans; Models, Biological; Mutagenesis; Oncogenes
PubMed: 1935129
DOI: No ID Found -
Biochemistry Oct 1998Described herein are detailed hydrolytic studies of a series of aziridinyl quinones, which trap nucleophiles when protonated. This study provided a compilation of the...
Described herein are detailed hydrolytic studies of a series of aziridinyl quinones, which trap nucleophiles when protonated. This study provided a compilation of the rate constants for nucleophile trapping and of the pKa values for the protonated aziridinyl quinones. A linear free energy relationship, including the antitumor agent DZQ, as well as other synthetic quinone derivatives, was obtained as a result of this study. Protonated DZQ has the relatively high pKa value of 3.8, which explains the enhanced cross-linking of DNA by DZQ and other related aziridinyl quinones at pH 4. The literature often shows aziridinyl quinone protonation occurring at the aziridinyl nitrogen, but the dependence of pKa values on quinone substituents indicates the presence of delocalization, which must arise from O-protonation. Also investigated were the DNA alkylation reactions of protonated aziridinyl quinones. At the outset of this study, we postulated that these "hard" electrophiles would alkylate the phosphate backbone of DNA. Bulk DNA is up to 35% alkylated by protonated aziridinyl quinones as judged by the incorporation of the quinone chromophore into the DNA. The presence of phosphate alkylation was verified by a 1H-31P NMR correlation experiment with DZQ-alkylated hexamer. Our modeling studies present a new picture of DZQ alkylation of DNA, where there is competition between N(7) and phosphate alkylation. The conclusions of this part of our study are that the phosphate backbone should be considered as a possible target of any DNA-alkylating agent and that an assessment of phosphate alkylation is best made with a 1H-31P NMR correlation experiment. Finally, the benzimidazole-based aziridinyl quinone 2 was observed to undergo aziridine ring opening followed by hydrolytic removal of the aminoethyl group from the quinone ring. This reaction was used to tag the phosphate backbone of DNA with aminoethyl groups. Such tags render anionic phosphates cationic and could also be employed as points of attachment for chromophores, spin labels, or other moieties to DNA.
Topics: Alkylating Agents; Alkylation; Aziridines; Benzoquinones; DNA; Esterification; Hydrolysis; Poly dA-dT; Polydeoxyribonucleotides; Sugar Phosphates
PubMed: 9790684
DOI: 10.1021/bi981204j -
Journal of the American Chemical Society Nov 2003A 9-aminoacridine conjugate of a silyl-protected bis(acetoxymethyl)phenol (bisQMP) was synthesized and evaluated as an inducible cross-linking agent of DNA to test our...
A 9-aminoacridine conjugate of a silyl-protected bis(acetoxymethyl)phenol (bisQMP) was synthesized and evaluated as an inducible cross-linking agent of DNA to test our ability to harness the chemistry of reactive quinone methide intermediates (QM). The acridine component was chosen for its ability to delivery an appendage to the major groove of DNA, and the silyl-protected component was chosen for its ability to generate two quinone methide equivalents in tandem upon addition of fluoride. This design created competition between reaction of (1) the 2-amino group of guanine that reacts irreversibly to form a stable QM adduct and (2) the more nucleophilic N7 group of guanine that reacts more efficiently but reversibly to form a labile QM adduct. This lability was apparently compensated by co-localization of the N7 group and QM in the major groove since the N7 adduct appeared to dominate the profile of products formed by duplex DNA. The controlling influence of acridine was also expressed in the sensitivity of the conjugate to ionic strength. High salt concentration inhibited covalent reaction just as it inhibits intercalation of the cationic acridine. As expected for QM formation, the presence of fluoride was indeed necessary for initiating reaction, and no direct benzylic substitution was observed. The conjugate also cross-linked DNA with high efficiency, forming one cross-link for every four alkylation events. Both alkylation and cross-linking products formed by duplex DNA were labile to hot piperidine treatment which led to approximately 40% strand scission and approximately 50% reversion to a material with an electrophoretic mobility equivalent to the parent DNA. All guanines exhibited at least some reactivity including those which were recalcitrant to cross-linking by an oligonucleotide-bisQMP conjugate designed for triplex formation [Zhou, G.; Pande, P.; Johnson, A. E.; Rokita, S. E. Bioorg. Med. Chem. 2001, 9, 2347-2354].
Topics: Alkylating Agents; Alkylation; Aminacrine; Cross-Linking Reagents; DNA; Indolequinones; Kinetics; Osmolar Concentration; Phenols; Structure-Activity Relationship; Substrate Specificity
PubMed: 14611237
DOI: 10.1021/ja036943o -
Redox Biology May 2022Overproduction of reactive oxygen species (ROS) drives inflammation and mutagenesis. However, the role of the DNA damage response in immune responses remains largely...
Overproduction of reactive oxygen species (ROS) drives inflammation and mutagenesis. However, the role of the DNA damage response in immune responses remains largely unknown. Here we found that stabilization of the mismatch repair (MMR) protein MSH6 in response to alkylation damage requires interactions with the molybdopterin synthase associating complex (MPTAC) and Ada2a-containing histone acetyltransferase complex (ATAC). Furthermore, MSH6 promotes sterol biosynthesis via the mevalonate pathway in a MPTAC- and ATAC-dependent manner. MPTAC reduces the source of alkylating agents (ROS). Therefore, the association between MMR proteins, MPTAC, and ATAC promotes anti-inflammation response and reduces alkylating agents. The inflammatory responses measured by xanthine oxidase activity are elevated in Lymphoblastoid Cell Lines (LCLs) from some Fragile X-associated disorders (FXD) patients, suggesting that alkylating agents are increased in these FXD patients. However, MPTAC is disrupted in LCLs from some FXD patients. In LCLs from other FXD patients, interaction between MSH6 and ATAC was lost, destabilizing MSH6. Thus, impairment of MPTAC and ATAC may cause alkylation damage resistance in some FXD patients.
Topics: Alkylating Agents; Alkylation; DNA Damage; DNA Repair; DNA-Binding Proteins; Humans; Reactive Oxygen Species; Sterols
PubMed: 35189552
DOI: 10.1016/j.redox.2022.102270 -
Progress in Clinical and Biological... 1990
Review
Topics: Alkylating Agents; Alkylation; Antineoplastic Agents; Benzyl Compounds; DNA; DNA Damage; Epoxy Compounds; Guanine; Mutagens; Stereoisomerism; Structure-Activity Relationship
PubMed: 2201980
DOI: No ID Found