共查询到20条相似文献,搜索用时 15 毫秒
1.
Fekry MI Szekely J Dutta S Breydo L Zang H Gates KS 《Journal of the American Chemical Society》2011,133(44):17641-17651
Molecular recognition and chemical modification of DNA are important in medicinal chemistry, toxicology, and biotechnology. Historically, natural products have revealed many interesting and unexpected mechanisms for noncovalent DNA binding and covalent DNA modification. The studies reported here characterize the molecular mechanisms underlying the efficient alkylation of duplex DNA by the Streptomyces-derived natural product leinamycin. Previous studies suggested that alkylation of duplex DNA by activated leinamycin (2) is driven by noncovalent association of the natural product with the double helix. This is striking because leinamycin does not contain a classical noncovalent DNA-binding motif, such as an intercalating unit, a groove binder, or a polycation. The experiments described here provide evidence that leinamycin is an atypical DNA-intercalating agent. A competition binding assay involving daunomycin-mediated inhibition of DNA alkylation by leinamycin provided evidence that activated leinamycin binds to duplex DNA with an apparent binding constant of approximately 4.3 ± 0.4 × 10(3) M(-1). Activated leinamycin caused duplex unwinding and hydrodynamic changes in DNA-containing solutions that are indicative of DNA intercalation. Characterization of the reaction of activated leinamycin with palindromic duplexes containing 5'-CG and 5'-GC target sites, bulge-containing duplexes, and 5-methylcytosine-containing duplexes provided evidence regarding the orientation of leinamycin with respect to target guanine residues. The data allow construction of a model for the leinamycin-DNA complex suggesting how a modest DNA-binding constant combines with proper positioning of the natural product to drive efficient alkylation of guanine residues in the major groove of duplex DNA. 相似文献
2.
Bando T Narita A Asada K Ayame H Sugiyama H 《Journal of the American Chemical Society》2004,126(29):8948-8955
Conjugates 12S and 12R of N-methylpyrrole (Py)-N-methylimidazole (Im) seven-ringed hairpin polyamide with both enantiomers of 1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one (CBI) were synthesized, and their DNA alkylating activity was examined. High-resolution denaturing gel electrophoresis revealed that 12S selectively and efficiently alkylated at one match sequence, 5'-TGACCA-3', in 450-bp DNA fragments. The selectivity and efficiency of the DNA alkylation by 12S were higher than those of the corresponding cyclopropapyrroloindole (CPI) conjugate, 11. In sharp contrast, another enantiomer, 12R, showed very weak DNA alkylating activity. Product analysis of the synthetic decanucleotide confirmed that the alkylating activity of 12S was comparable with 11 and that 12S had a significantly higher reactivity than 12R. The enantioselective reactivity of 12S and 12R is assumed to be due to the location of the alkylating cyclopropane ring of the CBI unit in the minor groove of the DNA duplex. Since the CBI unit can be synthesized from commercially available 1,3-naphthalenediol, the present results open up the possibility of large-scale synthesis of alkylating Py-Im polyamides for facilitating their use in future animal studies. 相似文献
3.
4.
5.
W F Veldhuyzen A J Shallop R A Jones S E Rokita 《Journal of the American Chemical Society》2001,123(45):11126-11132
Alkylating agents that react through highly electrophilic quinone methide intermediates often express a specificity for the weakly nucleophilic exocyclic amines of deoxyguanosine (dG N(2)) and deoxyadenosine (dA N(6)) in DNA. Investigations now indicate that the most nucleophilic site of dA (N1) preferentially, but reversibly, conjugates to a model ortho-quinone methide. Ultimately, the thermodynamically stable dA N(6) isomer accumulates by trapping the quinone methide that is transiently regenerated from collapse of the dA N1 adduct. Alternative conversions of the dA N1 to the dA N(6) derivative by a Dimroth rearrangement or other intramolecular processes are not competitive under neutral conditions, as demonstrated by studies with [6-(15)N]-dA. Both a model quinone methide precursor and its dA N1 adduct yield a similar profile of deoxynucleoside products when treated with an equimolar mixture of dC, dA, dG, and T. Consequently, the most readily observed products of DNA modification resulting from reversible reactions may reflect thermodynamic rather than kinetic selectivity. 相似文献
6.
Sequence specific alkylation of DNA by hairpin pyrrole-imidazole polyamide conjugates 总被引:4,自引:0,他引:4
BACKGROUND: Pyrrole-imidazole polyamides are synthetic ligands that recognize predetermined sequences in the minor groove of DNA with affinities and specificities comparable to those of DNA-binding proteins. As a result of their DNA-binding properties, polyamides could deliver reactive moieties for covalent reaction at specific DNA sequences and thereby inhibit DNA-protein interactions. Site-specific alkylation of DNA could be a useful tool for regulating gene expression. As a minimal first step, we set out to design and synthesize a class of hairpin polyamides equipped with DNA alkylating agents and characterize the specificity and yield of covalent modification. RESULTS: Bis(dichloroethylamino)benzene derivatives of the well-characterized chlorambucil (CHL) were attached to the gamma turn of an eight-ring hairpin polyamide targeted to the HIV-1 promoter. We found that a hairpin polyamide-CHL conjugate binds and selectively alkylates predetermined sites in the HIV promoter at subnanomolar concentrations. Cleavage sites were determined on both strands of a restriction fragment containing the HIV-1 promoter, revealing good specificity and a high yield of alkylation. CONCLUSIONS: The ability of polyamide-CHL conjugates to sequence specifically alkylate double-stranded DNA in high yield and at low concentrations sets the stage for testing their use as regulators of gene expression in cell culture and ultimately in complex organisms. 相似文献
7.
Minoshima M Bando T Sasaki S Shinohara K Shimizu T Fujimoto J Sugiyama H 《Journal of the American Chemical Society》2007,129(17):5384-5390
The sequence-specific DNA alkylation by conjugates 4 and 5, which consist of N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides and 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) linked with an indole linker, was investigated in the absence or presence of partner Py-Im polyamide 6. High-resolution denaturing polyacrylamide gel electrophoresis revealed that conjugate 4 alkylates DNA at the sequences 5'-(A/T)GCCTA-3' through hairpin formation, and alkylates 5'-GGAAAGAAAA-3' through an extended binding mode. However, in the presence of partner Py-Im polyamide 6, conjugate 4 alkylates DNA at a completely different sequence, 5'-AGGTTGTCCA-3'. Alkylation of 4 in the presence of 6 was effectively inhibited by a competitor 7. Surface plasmon resonance (SPR) results indicated that conjugate 4 does not bind to 5'-AGGTTGTCCA-3', whereas 6 binds tightly to this sequence. The results suggest that alkylation proceeds through heterodimer formation, indicating that this is a general way to expand the recognition sequence for DNA alkylation by Py-Im seco-CBI conjugates. 相似文献
8.
Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3df,p)//B3LYP/6-31G level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol-mediated activation of leinamycin involves initial attack of thiolate at the S2'-position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate (3). 相似文献
9.
Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine. 相似文献
10.
Estimation of the products of DNA alkylation 总被引:1,自引:0,他引:1
A O Olson 《Journal of chromatography. A》1968,35(2):292-294
11.
We have synthesized an enantiomeric pair of novel DNA alkylating agents consisting of a naphthaldiimide intercalator and a chiral epoxy side chain. These naphthaldiimide derivatives have high DNA binding affinity and selectively alkylate 5'G of the GG steps for (S)-epoxide and 3'G for (R)-epoxide. 相似文献
12.
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]. 相似文献
13.
Ákos Szilágyi 《Tetrahedron letters》2004,45(22):4307-4309
A simple synthesis of 1,2-dithiolan-3-ones from α,β-unsaturated thiophenyl esters has been elaborated. With the aim of introducing the biologically active 1,2-dithiolan-3-one-1-oxide moiety of leinamycin into a nucleoside, the method was successfully applied to thymidine-5′-aldehyde. 相似文献
14.
B. Ya. Eryshev Yu. I. Smushkevich N. N. Suvorov 《Chemistry of Heterocyclic Compounds》1985,21(4):433-435
The alkylation of indole by polyesters of -hydroxyalkanoic acids was studied. The optimum conditions and ratios of the reacting substances were found, and a number of -(3-indolyl)alkanoic acids were obtained.See [1] for communication 126.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 519–521, April, 1985. 相似文献
15.
Bando T Narita A Saito I Sugiyama H 《Chemistry (Weinheim an der Bergstrasse, Germany)》2002,8(20):4781-4790
New hairpin polyamide-CPI (CPI = cyclopropylpyrroloindole) conjugates, compounds 12-14, were synthesized and their DNA-alkylating activities compared with the previously prepared hairpin polyamide, compound 1, by high-resolution denaturing gel electrophoresis with 450 base pair (bp) DNA fragments and by HPLC product analysis of the synthetic decanucleotide. In accord with our previous results, alkylation by compound 1 occurred predominantly at the G moiety of the sequence 5'-AGTCAG-3' (site 3). However, compound 12, in which the structure of the alkylating moiety of compound 1 is replaced with segment A of duocarmycin A DU-86 (CPI), did not show any DNA alkylating activity. In clear contrast, the hairpin CPI conjugate 13, which differs from compound 1 in that it lacks one Py unit and possesses a vinyl linker, alkylated the A of 5'-AGTCAG-3' (site 3) efficiently at nanomolar concentrations. Alkylation by compound 14, which has a vinyl linker, occurred at the A of 5'-AGTCCA-3' (site 6) and at several minor alkylation sites, including mismatch alkylation at A of 5'-TCACAA-3' (site 2). The significantly different reactivity of the alkylating hairpin polyamides 1, 12, 13, and 14 was further confirmed by HPLC product analysis by using a synthetic decanucleotide. The results suggest that hairpin polyamide--CPI conjugate 13 alkylates effectively according to Dervan's pairing rule, and with a new mode of recognition in which the Im-vinyl linker (L) pair targets G-C base pairs. These results demonstrate that incorporation of the vinyl-linker pairing with Im dramatically improves the reactivity of hairpin polyamide--CPI conjugates. 相似文献
16.
DNA-binding small molecules are an important source of anticancer therapeutics that display a diverse array of mechanisms of action. Synthetic studies on the new DNA-alkylating natural product yatakemycin, detailed in this Highlight, have served to reassign its structure, assign the absolute stereochemistry, and provide access to yatakemycin and a series of structural analogues for biological evaluation. Studies on the DNA alkylation properties of (+)-and ent-(-)-yatakemycin and related analogues have demonstrated the enhanced DNA alkylation properties of this class of agents and provided insight into their interaction with DNA. 相似文献
17.
I. K. Shprunka L. Ya. Binduka T. V. Shidlovskaya R. A. Zhagat 《Chemistry of Natural Compounds》1980,16(2):184-187
Alkylasparaginases have been obtained with the far-reaching modification of 1–10 lysine residues per subunit of the enzyme. It has been established that alkylation does not affect the stability of the enzyme, and the change in the pH optimum of the catalytic action is due to the chemical nature of the alkyl substituent.Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 232–235, March–April, 1980. 相似文献
18.
Cimino P Bifulco G Riccio R Gomez-Paloma L Barone V 《Organic & biomolecular chemistry》2006,4(7):1242-1251
The role of local geometric and stereo-electronic effects in tuning the alkylation of DNA by duocarmycins has been analyzed by an integrated computational tool rooted in the density functional theory and the polarizable continuum model. Our study points out that together with steric accessibility, different electronic delocalisations also contribute to determine the higher reactivity of adenine with respect to guanine. Also the effect of the methyl ester group on the alkylating agent has an electronic origin. Furthermore, deviations from the planarity in the drug structure (conformational catalysis) could be less important than currently accepted since, according to our computations, compounds with strongly different reactivity have nearly constant and very similar out of plane distortions before and after the reaction. Model computations suggest, instead, that specific non covalent interactions could discriminate between different drugs selectively reducing some activation energies with respect to the corresponding processes in solution. 相似文献
19.
A critical branch point in mucin-type oligosaccharides is the beta 1-->3 glycosidic linkage to the core alpha-N-acetylgalactosamine (GalNAc) residue. We report here a strategy for the synthesis of O-linked glycopeptide analogues that replaces this linkage with a thioether amenable to construction by chemoselective ligation. The key building block was a 2-azido-3-thiogalactose-Thr analogue that was incorporated into a peptide by fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Higher order oligosaccharides were readily generated by alkylation of the corresponding 3-thioGalNAc with N-bromoacetamido sugars. The rapid assembly of "core 1"and "core 3" O-linked glycopeptide mimetics was accomplished in this fashion. 相似文献
20.