Synthesis and Biological Studies of Inducible DNA Cross‐Linking Agents

Weng, Xiaocheng; Ren, Lei; Weng, Liwei; Huang, Jing; Zhu, Shugao; Zhou, Xiang; Weng, Linhong

doi:10.1002/ange.200700844

Cited by 24 publications

(17 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most relevant to the current study was the design of bisfunctional precursors capable of generating two interrelated QM intermediates (bisQM) in series. These derivatives act as a potent crosslinker of DNA with an enviable ratio of crosslinking to monoalkylation 32,[48][49][50] . The reversible nature of reaction additionally prolongs the effective lifetime of the electrophile many-fold and can maintain interstrand crosslinking while still permitting strand exchange (Fig.…”

Section: Resultsmentioning

confidence: 99%

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Fakhari

Rokita

2014

Nat Commun

View full text Add to dashboard Cite

DNA has previously served as an excellent scaffold for molecular transport based on its noncovalent base pairing to assemble both stationary and mobile elements. Use of DNA can now be extended to transport systems based on reversible covalent chemistry. Autonomous and bipedal-like migration of crosslinking within helical DNA is made possible by tandem exchange of a quinone methide intermediate. In this report, net transport is illustrated to proceed over 10 base pairs. This process is driven towards its equilibrium distribution of crosslinks and consumes neither the walker nor the track irreversibly. Successful migration requires an electron-rich quinone methide to promote its regeneration and a continuous array of nucleophilic sites along its DNA track. Accordingly, net migration can be dramatically influenced by the presence of noncanonical structures within duplex DNA as demonstrated with a backbone nick and extrahelical bulge.

show abstract

Section: Resultsmentioning

confidence: 99%

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Fakhari

Rokita

2014

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Quinone methides are important intermediates in a large number of DNA cross-linking and alkylating processes. [18][19][20][21][22][23][24][25][26][27][28] Several methods to generate o-QMs from various precursors Abstract: A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N + Me 3 Br À ) have been synthesized. The substituent effects on their reactivity with H 2 O 2 and formation of quinone methide (QM) have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Substituent Effects on Oxidation‐Induced Formation of Quinone Methides from Arylboronic Ester Precursors

Cao

Christiansen

Peng

2013

Chemistry A European J

View full text Add to dashboard Cite

A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N(+)Me3Br(-)) have been synthesized. The substituent effects on their reactivity with H2O2 and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used to determine the reaction mechanism and QM formation, respectively. QMs were not generated during oxidative cleavage of the boronic esters but by subsequent transformation of the phenol products under physiological conditions. The oxidative deboronation is facilitated by electron-withdrawing substituents, such as aromatic F, NO2, or benzylic N(+)Me3Br(-), whereas electron-donating substituents or a better leaving group favor QM generation. Compounds containing an aromatic CH3 or OMe group, or a good leaving group (Br), efficiently generate QMs under physiological conditions. Finally, a quantitative relationship between the structure and activity has been established for the arylboronic esters by using a Hammett plot. The reactivity of the arylboronic acids/esters and the inhibition or facilitation of QM formation can now be predictably adjusted. This adjustment is important as some applications may benefit and others may be limited by QM generation.

show abstract

“…o -Quinone intermediate, an actively potent DNA cross-linking unit resulted from a catechol precursor upon oxidation, has been proved to possess good cross-linking activity toward duplex DNAs without resulting in G-quadruplex cross-linked25. A superiority of the o -quinone mediated DNA cross-linking was that it could be readily stimulated by tyrosinase, which is highly expressed in some malignant tumors26272829, thus bringing in good cell selectivity. Taken together, the catechol moiety was an ideal scaffold that could fit multifaceted requirements.…”

mentioning

confidence: 99%

Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy

Yuan

Tian

Chen

et al. 2013

Sci Rep

Self Cite

View full text Add to dashboard Cite

Existence of G-quadruplex DNA in vivo always attract widespread interest in the field of biology and biological chemistry. We reported our findings for the existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy. Probes for selective G-quadruplex cross-linking was designed and synthesized that show high selectivity for G-quadruplex cross-linking. Further biological studies demonstrated its good inhibition activity against murine melanoma cells. To further investigate if G-quadruplex DNA was formed in vivo and as the target, a derivative was synthesized and pull-down process toward chromosome DNAs combined with circular dichroism and high throughput deep sequencing were performed. Several simulated intracellular conditions, including X. laevis oocytes, Ficoll 70 and PEG, was used to investigate the compound's pure cross-linking ability upon preformed G-quadruplex. Thus, as a potent G-quadruplex cross-linking agent, our strategy provided both valuable evidence of G-quadruplex structures in vivo and intense potential in anti-cancer therapy.

show abstract

Synthesis and Biological Studies of Inducible DNA Cross‐Linking Agents

Cited by 24 publications

References 33 publications

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Substituent Effects on Oxidation‐Induced Formation of Quinone Methides from Arylboronic Ester Precursors

Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy

Contact Info

Product

Resources

About