Comparison of a DSB-120 DNA interstrand cross-linked adduct with the corresponding bis-tomaymycin adduct: An example of a successful template-directed approach to drug design based upon the monoalkylating compound tomaymycin

John A. Mountzouris, Jeh Jeng Wang, David Thurston, Laurence Hurley

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Abstract

The interstrand cross-linked DSB-120-d(CICG*ATCICG)2 DNA adduct (* indicates covalently modified guanine) was examined by two-dimensional NMR and compared to the bis-tomaymycin adduct on the same oligomer. Tomaymycin and DSB-120 form self-complementary adducts with the d(CICGATCICG)2 duplex sequence in which the covalent linkage sites occur between C11 of either drug and the exocyclic 2-amino group of the single reactive guanine on each strand of d(CICGATCICG)2. In the case of DSB-120, this is evidence for the formation of a guanine-guanine DNA interstrand cross-link. Both drugs show formation of an S stereochemistry at the covalent linkage site with an associated 3′ orientation. While the majority of DNA in these adducts appears to be B-form, DSB-120 interstrand cross-linking induces atypical properties in the 81 nucleotide, indicated by broadening of the 8IH2 proton resonance, non-C2′ endo sugar geometry, and unusually weak internucleotide NOE connectivity to the 7C nucleotide. Tomaymycin does not produce this regional dislocation. For tomaymycin, while there are strong NOE connectivities from protons on the five-membered ring to the 8IH2 proton on the floor of the minor groove, the equivalent internucleotide connectivities in DSB-120 are weaker. This indicates that the tomaymycin tail is close to the floor of the minor groove, while the five-membered ring of DSB-120 is more shallowly immersed, perhaps due to strain from cross-linking with a very short linker unit. Last, the conformational stresses induced on the duplex by DSB-120 appear to make the region of covalent attachment more accessible to solvent than is the case for tomaymycin. The 4GN2Hb resonance appears in 100% D2O on the tomaymycin adduct but is only observed in 90% H2O/10% D2O for the DSB-120 adduct. On the basis of these results, the strategies for template-directed DNA cross-linker design are assessed.

Original languageEnglish (US)
Pages (from-to)3132-3140
Number of pages9
JournalJournal of Medicinal Chemistry
Volume37
Issue number19
StatePublished - 1994
Externally publishedYes

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Drug Design
DNA
Guanine
Pharmaceutical Preparations
Protons
DNA Adducts
Nucleotides
Stereochemistry
DSB 120
tomaymycin
Oligomers
Sugars
Nuclear magnetic resonance
Geometry

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{2213cac01bda49e182549ac069b6391f,
title = "Comparison of a DSB-120 DNA interstrand cross-linked adduct with the corresponding bis-tomaymycin adduct: An example of a successful template-directed approach to drug design based upon the monoalkylating compound tomaymycin",
abstract = "The interstrand cross-linked DSB-120-d(CICG*ATCICG)2 DNA adduct (* indicates covalently modified guanine) was examined by two-dimensional NMR and compared to the bis-tomaymycin adduct on the same oligomer. Tomaymycin and DSB-120 form self-complementary adducts with the d(CICGATCICG)2 duplex sequence in which the covalent linkage sites occur between C11 of either drug and the exocyclic 2-amino group of the single reactive guanine on each strand of d(CICGATCICG)2. In the case of DSB-120, this is evidence for the formation of a guanine-guanine DNA interstrand cross-link. Both drugs show formation of an S stereochemistry at the covalent linkage site with an associated 3′ orientation. While the majority of DNA in these adducts appears to be B-form, DSB-120 interstrand cross-linking induces atypical properties in the 81 nucleotide, indicated by broadening of the 8IH2 proton resonance, non-C2′ endo sugar geometry, and unusually weak internucleotide NOE connectivity to the 7C nucleotide. Tomaymycin does not produce this regional dislocation. For tomaymycin, while there are strong NOE connectivities from protons on the five-membered ring to the 8IH2 proton on the floor of the minor groove, the equivalent internucleotide connectivities in DSB-120 are weaker. This indicates that the tomaymycin tail is close to the floor of the minor groove, while the five-membered ring of DSB-120 is more shallowly immersed, perhaps due to strain from cross-linking with a very short linker unit. Last, the conformational stresses induced on the duplex by DSB-120 appear to make the region of covalent attachment more accessible to solvent than is the case for tomaymycin. The 4GN2Hb resonance appears in 100{\%} D2O on the tomaymycin adduct but is only observed in 90{\%} H2O/10{\%} D2O for the DSB-120 adduct. On the basis of these results, the strategies for template-directed DNA cross-linker design are assessed.",
author = "Mountzouris, {John A.} and Wang, {Jeh Jeng} and David Thurston and Laurence Hurley",
year = "1994",
language = "English (US)",
volume = "37",
pages = "3132--3140",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "19",

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T1 - Comparison of a DSB-120 DNA interstrand cross-linked adduct with the corresponding bis-tomaymycin adduct

T2 - An example of a successful template-directed approach to drug design based upon the monoalkylating compound tomaymycin

AU - Mountzouris, John A.

AU - Wang, Jeh Jeng

AU - Thurston, David

AU - Hurley, Laurence

PY - 1994

Y1 - 1994

N2 - The interstrand cross-linked DSB-120-d(CICG*ATCICG)2 DNA adduct (* indicates covalently modified guanine) was examined by two-dimensional NMR and compared to the bis-tomaymycin adduct on the same oligomer. Tomaymycin and DSB-120 form self-complementary adducts with the d(CICGATCICG)2 duplex sequence in which the covalent linkage sites occur between C11 of either drug and the exocyclic 2-amino group of the single reactive guanine on each strand of d(CICGATCICG)2. In the case of DSB-120, this is evidence for the formation of a guanine-guanine DNA interstrand cross-link. Both drugs show formation of an S stereochemistry at the covalent linkage site with an associated 3′ orientation. While the majority of DNA in these adducts appears to be B-form, DSB-120 interstrand cross-linking induces atypical properties in the 81 nucleotide, indicated by broadening of the 8IH2 proton resonance, non-C2′ endo sugar geometry, and unusually weak internucleotide NOE connectivity to the 7C nucleotide. Tomaymycin does not produce this regional dislocation. For tomaymycin, while there are strong NOE connectivities from protons on the five-membered ring to the 8IH2 proton on the floor of the minor groove, the equivalent internucleotide connectivities in DSB-120 are weaker. This indicates that the tomaymycin tail is close to the floor of the minor groove, while the five-membered ring of DSB-120 is more shallowly immersed, perhaps due to strain from cross-linking with a very short linker unit. Last, the conformational stresses induced on the duplex by DSB-120 appear to make the region of covalent attachment more accessible to solvent than is the case for tomaymycin. The 4GN2Hb resonance appears in 100% D2O on the tomaymycin adduct but is only observed in 90% H2O/10% D2O for the DSB-120 adduct. On the basis of these results, the strategies for template-directed DNA cross-linker design are assessed.

AB - The interstrand cross-linked DSB-120-d(CICG*ATCICG)2 DNA adduct (* indicates covalently modified guanine) was examined by two-dimensional NMR and compared to the bis-tomaymycin adduct on the same oligomer. Tomaymycin and DSB-120 form self-complementary adducts with the d(CICGATCICG)2 duplex sequence in which the covalent linkage sites occur between C11 of either drug and the exocyclic 2-amino group of the single reactive guanine on each strand of d(CICGATCICG)2. In the case of DSB-120, this is evidence for the formation of a guanine-guanine DNA interstrand cross-link. Both drugs show formation of an S stereochemistry at the covalent linkage site with an associated 3′ orientation. While the majority of DNA in these adducts appears to be B-form, DSB-120 interstrand cross-linking induces atypical properties in the 81 nucleotide, indicated by broadening of the 8IH2 proton resonance, non-C2′ endo sugar geometry, and unusually weak internucleotide NOE connectivity to the 7C nucleotide. Tomaymycin does not produce this regional dislocation. For tomaymycin, while there are strong NOE connectivities from protons on the five-membered ring to the 8IH2 proton on the floor of the minor groove, the equivalent internucleotide connectivities in DSB-120 are weaker. This indicates that the tomaymycin tail is close to the floor of the minor groove, while the five-membered ring of DSB-120 is more shallowly immersed, perhaps due to strain from cross-linking with a very short linker unit. Last, the conformational stresses induced on the duplex by DSB-120 appear to make the region of covalent attachment more accessible to solvent than is the case for tomaymycin. The 4GN2Hb resonance appears in 100% D2O on the tomaymycin adduct but is only observed in 90% H2O/10% D2O for the DSB-120 adduct. On the basis of these results, the strategies for template-directed DNA cross-linker design are assessed.

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