Chemical modification of deoxyribonucleic acids: a direct study by carbon-13 nuclear magnetic resonance spectroscopy

Chang, Ching Jer; Gomes, Jose DaSilva; Byrn, Stephen R.

doi:10.1021/jo00174a002

Cited by 26 publications

(34 citation statements)

References 8 publications

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“…18 Careful examination of spectral data (NMR, MS) of thymine and uracil showed that they are similar to the data reported for 9 and 10, isolated by Mishra et al 19 (9) from the sponge Suberites vestigium and Parameswaran et al 20 (9 and 10) from the sponge Tedania anhelans.…”

Section: Resultssupporting

confidence: 74%

New Manzamine Alkaloids with Activity against Infectious and Tropical Parasitic Diseases from an Indonesian Sponge

et al. 2003

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Eleven manzamine type alkaloids, two β-carbolines, and five nucleosides have been isolated from an Indonesian sponge. Among these are the previously characterized 12,34-oxamanzamine A, 12,34-oxamanzamine E, manzamine A (1), 8-hydroxymanzamine A, 6-deoxymanzamine X, manzamine E (2), manzamine X, manzamine F (4), norharman, thymine, 2′,3′-didehydro-2′,3′-dideoxyuridine, uracil, thymidine, and 2′-deoxyuridine. The structures for the five new compounds have been assigned as 32,33-dihydro-31-hydroxymanzamine A (3), 32,33-dihydro-6-hydroxymanzamine A-35-one (5), des-N-methylxestomanzamine A (6), 32,33-dihydro-6,31-dihydroxymanzamine A (7), and 1,2,3,4-tetrahydronorharman-1-one (8), on the basis of NMR and X-ray data. The bioactivity and SAR of the manzamines against malaria, TB, and leishmania are also presented. The structural revision of two previously reported pyrazoles as uracil and thymine is also discussed.Manzamines are unique β-carboline alkaloids isolated from Indo-Pacific sponges and characterized by having an intricate nitrogen-containing polycyclic system. In 1986, Higa and co-workers first reported manzamine A from the Okinawan sponge of the genus Haliclona. 1 These compounds exhibit a diverse range of bioactivities including cytotoxicity, 1 insecticidal, 2 and antibacterial 3 as well as the exciting curative activity against malaria in animal models. 4,5 Since the first report of manzamine A, an additional 40 manzamine-type alkaloids have been reported from nine different sponge genera. 6,7 In our continuing search for manzamine-related alkaloids with significant activity against infectious diseases, we have identified several novel manzamine alkaloids from an Indonesian sponge, and herein we describe their structure determination and biological activity. *To whom correspondence should be addressed. Tel: (662) 915-5730. Fax: (662) 915-6975. mthamann@olemiss.edu. Supporting Information Available: Copies of 1 H and 13 C NMR spectra for all new compounds, HMQC spectra for 3, 5-7, HMBC spectra for 5-8, and X-ray data for 3. This material is available free of charge via the Internet at http://pubs.acs.org. (Table 1) includes aromatic proton resonances similar to those of manzamine E. 12 Spectral data of how 3 differs from manzamine E (2) includes the presence of 13 CH carbons (manzamine E has 12 CH carbons) and the absence of the low-field C-31 carbonyl carbon signal of manzamine E. In place of the carbonyl carbon compound 3 has a signal at 70.9 ppm, which correlates with a multiplet at 4.05 ppm in the HMQC spectrum. The presence of this new OH-functionality is confirmed by a number of long-range 1 H-13 C correlations H 2 -29 and H 2 -33 to C-31, Figure 1 HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript C-12, C-24, C-25, C-26, and C-34 of 3 were elucidated to be the same as those of manzamine E by NOESY data as well as comparable 13 C chemical shifts. In addition both compounds were isolated from the same sponge and possessed dextrorotation. The relative config...

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Section: Resultssupporting

confidence: 74%

New Manzamine Alkaloids with Activity against Infectious and Tropical Parasitic Diseases from an Indonesian Sponge

et al. 2003

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“…Of the other nitrogens on dA, only reaction at N1 would produce a product with the observed chemical behavior due to its ability to isomerize to an N6-alkylamino derivative (Scheme 5). 7,30,31 Although reaction at N1-dA is unexpected based upon inspection of molecular models, this nitrogen is more nucleophilic than the N7-dA 28. Reaction at N1-dA requires that the Watson–Crick duplex undergo local melting.…”

Section: Resultsmentioning

confidence: 99%

Interstrand Cross-Link Formation in Duplex and Triplex DNA by Modified Pyrimidines

Peng

Hong²,

Li³

et al. 2008

J. Am. Chem. Soc.

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DNA interstrand cross-links have important biological consequences and are useful biotechnology tools. Phenylselenyl substituted derivatives of thymidine (1) and 5-methyl-2′-deoxycytidine (5) produce interstrand cross-links in duplex DNA when oxidized by NaIO 4 . The mechanism involves a [2,3]-sigmatropic rearrangement of the respective selenoxides to the corresponding methide type intermediates, which ultimately produce the interstrand cross-links. Determination of the rate constants for the selenoxide rearrangements indicates that the rate-determining step for cross-linking is after methide formation. Cross-linking by the thymidine derivative in duplex DNA shows a modest kinetic preference when flanked by pyrimidines as opposed to purines. In contrast, the rate constant for cross-link formation from 5 opposite dG in duplex DNA is strongly dependent upon the flanking sequence and, in general, is at least an order of magnitude slower than that for 1 in an otherwise identical sequence. Introduction of mispairs at the base pairs flanking 5 or substitution of the opposing dG by dI significantly increases the rate constant and yield for cross-linking, indicating that stronger hydrogen bonding between the methide derived from it and dG compared to dA and the respective electrophile derived from 1 limits reaction by increasing the barrier to rotation into the required syn-conformation. Incorporation of 1 or 5 in triplex forming oligonucleotides (TFOs) that utilize Hoogsteen base pairing also yields interstrand cross-links. The dC derivative produces ICLs approximately 10× faster than the thymidine derivative when incorporated at the 5′-termini of the TFOs and higher yields when incorporated at internal sites. The slower, less efficient ICL formation emanating from 1 is attributed to reaction at N1-dA, which requires local melting of the duplex. In contrast, 5 produces cross-links by reacting with N7-dG. The cross-linking reactions of 1 and 5 illustrate the versatility and utility of these molecules as mechanistic probes and tools for biotechnology.DNA alkylation is a common chemical process that is useful as a chemical tool but can also have biological consequences. For instance, alkylating agents are employed in the laboratory for determining DNA structure. However, alkylated DNA can be genotoxic and/or cytotoxic. 1 In addition, a number of molecules, including some antitumor agents, react with DNA by forming covalent bonds to the opposing strands. 2 The cross-linked strands are strong blocks to replication and are cytotoxic if unrepaired. 3 Modified oligonucleotides containing alkylating agents have also been used to form interstrand cross-links in duplex and triplex DNA. 4-6 We recently described a modified thymidine (1) that forms stable base pairs with dA and produces interstrand cross-links (ICLs) (4a, 4b) in duplex DNA under mild oxidative conditions (Scheme 1). 7-9 The cross-linking reaction is unusual in that like the antitumor agent N,N′-bis E-mail: mgreenberg@jhu.edu. † Johns Hopkins University. ‡ N...

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“…We also wanted to ascertain whether the uncharged lesions m1G and m3T, which are structurally analogous with respect to the alkylated position of m1A and m3C, would also be substrates for AlkB. The m1A, m3C, and e3C lesions in the present study are preferentially formed by alkylating agents in single-stranded DNA and have been detected in vitro (5,6,(12)(13)(14)(15)(16)(17)(18) and in vivo (12,17,(19)(20)(21)(22)(23)(24). Although less prevalent, m1G lesions have also been found in vitro (16) and in vivo (19), and m3T in vitro (12,13,16,18,25) and in vivo (12,25).…”

mentioning

confidence: 85%

Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli

Delaney

Essigmann²

2004

Proc. Natl. Acad. Sci. U.S.A.

228

362

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AlkB repairs 1-alkyladenine and 3-methylcytosine lesions in DNA by directly reversing the base damage. Although repair studies with randomly alkylated substrates have been performed, the miscoding nature of these and related individually alkylated bases and the suppression of mutagenesis by AlkB within cells have not yet been explored. Here, we address the miscoding potential of 1-methyldeoxyadenosine (m1A), 3-methyldeoxycytidine (m3C), 3-ethyldeoxycytidine (e3C), 1-methyldeoxyguanosine (m1G), and 3-methyldeoxythymidine (m3T) by synthesizing single-stranded vectors containing each alkylated base, followed by vector passage through Escherichia coli. In SOS ؊ , AlkB-deficient cells, m1A was only 1% mutagenic; however, m3C and e3C were 30% mutagenic, rising to 70% in SOS ؉ cells. In contrast, the mutagenicity of m1G and m3T in AlkB ؊ cells dropped slightly when SOS polymerases were expressed (m1G from 80% to 66% and m3T from 60% to 53%). Mutagenicity was abrogated for m1A, m3C, and e3C in wild-type (AlkB ؉ ) cells, whereas m3T mutagenicity was only partially reduced. Remarkably, m1G mutagenicity was also eliminated in AlkB ؉ cells, establishing it as a natural AlkB substrate. All lesions were blocks to replication in AlkB-deficient cells. The m1A, m3C, and e3C blockades were completely removed in wild-type cells; the m1G blockade was partially removed and that for m3T was unaffected by the presence of AlkB. All lesions demonstrated enhanced bypass when SOS polymerases were induced. This work provides direct evidence that AlkB suppresses both genotoxicity and mutagenesis by physiologically realistic low doses of 1-alkylpurine and 3-alkylpyrimidine DNA damage in vivo.AlkB ͉ DNA repair ͉ DNA alkylation

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Chemical modification of deoxyribonucleic acids: a direct study by carbon-13 nuclear magnetic resonance spectroscopy

Cited by 26 publications

References 8 publications

New Manzamine Alkaloids with Activity against Infectious and Tropical Parasitic Diseases from an Indonesian Sponge

New Manzamine Alkaloids with Activity against Infectious and Tropical Parasitic Diseases from an Indonesian Sponge

Interstrand Cross-Link Formation in Duplex and Triplex DNA by Modified Pyrimidines

Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli

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