Few constraints limit the design of quinone methide-oligonucleotide self-adducts for directing DNA alkylation

Rossiter, Clifford S.; Modica, Emilia; Kumar, Dalip; Rokita, Steven E.

doi:10.1039/c0cc03317k

Cited by 31 publications

(31 citation statements)

References 23 publications

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“…The rate and final yield of target alkylation can be influenced by the profile of species comprising the self adduct as tested previously by DNA forming hairpin and random coiled structures (13). Early studies on a low molecular weight model QM illustrated a rapid formation of reversible nucleobase adducts through reaction with strong nitrogen nucleophiles such as dG N7, dA N1 and dC N3 that also act as strong leaving groups for QM regeneration (15).…”

Section: Resultsmentioning

confidence: 97%

“…Previous studies with DNA-QM conjugates indicated that most any sequence is capable of forming self adducts and transferring its QM to a complementary target (13). Self adducts are likely formed as a heterogeneous mixture of species as a result of QM capture by the various strong nucleophiles present in the attached sequence-directing strand.…”

Section: Resultsmentioning

confidence: 99%

“…Self adducts are likely formed as a heterogeneous mixture of species as a result of QM capture by the various strong nucleophiles present in the attached sequence-directing strand. Systematic evaluation of such strands lacking A, G or C alternatively demonstrated that no individual nucleobase was critical for generating self adducts or effecting their subsequent alkylation of complementary strands (13). Only T remains inert to this QM, and a QMP conjugate with (T) 10 is the sole derivative observed to date that does not have the capacity to form a self adduct (12).…”

Section: Resultsmentioning

confidence: 99%

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Inducible Alkylation of DNA by a Quinone Methide–Peptide Nucleic Acid Conjugate

Liu

Rokita

2012

Biochemistry

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The reversibility of alkylation by a quinone methide intermediate (QM) avoids the irreversible consumption that plagues most reagents based on covalent chemistry and allows for site specific reaction that is controlled by the thermodynamics rather than kinetics of target association. This characteristic was originally examined with an oligonucleotide QM conjugate but broad application depends on alternative derivatives that are compatible with a cellular environment. Now, a peptide nucleic acid (PNA) derivative has been constructed and shown to exhibit an equivalent ability to delivery the reactive QM in a controlled manner. This new conjugate demonstrates high selectivity for a complementary sequence of DNA even when challenged with an alternative sequence containing a single T/T mismatch. Alkylation of non-complementary sequences is only possible when a template strand is present to co-localize the conjugate and its target. For efficient alkylation in this example, a single-stranded region of the target is required adjacent to the QM conjugate. Most importantly, the intrastrand self adducts formed between the PNA and its attached QM remained active and reversible over more than eight days in aqueous solution prior to reaction with a chosen target added subsequently.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Inducible Alkylation of DNA by a Quinone Methide–Peptide Nucleic Acid Conjugate

Liu

Rokita

2012

Biochemistry

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“…QM formation and regeneration are exquisitely sensitive to electronic effects as evident from the five orders of magnitude separating rate constants for QMs differing by a single substituent 31,40 . Although the reversibility of QM reaction may complicate detection of their adducts formed by xenobiotic metabolism of certain drugs and food additives [41][42][43] , the reversibility has allowed for the construction of target-inducible and site-selective alkylating agents [44][45][46] . Prior model studies indicated that the strongest nucleophiles of DNA (G N7, A N1 and C N3) are alkylated by QMs most readily but their resulting adducts dissipate over time as the weakly nucleophilic nitrogens (G N 2 and A N 6 ) and water began to trap the regenerated QM irreversibly 43,47 .…”

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confidence: 99%

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

Fakhari

Rokita

2014

Nat Commun

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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.

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“…guanina u položaju N-1, N-2 ili N-7, adenina u položaju N-6, citozina u N-4 ili timina u položaju N-3 89 . Ovim mehanizmom, primera radi, deluju mitomicin, porfiromicin, karbazilhinon 90 .…”

Section: Interakcije Avarona I Njegovih Derivata Sa Plazmidima Pbr322unclassified

Investigation of interactions of biologically active quinone avarone and its derivates with lysozyme, linear and circular deoxyribonucleic acid

Beogradu¹,

Fakultet²,

Novaković³

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_________________________________ Datum odbrane:i Ova doktorska disertacija urađena je u laboratorijama Hemijskog fakulteta i IHTMCentra za hemiju, Univerziteta u Beogradu.Rad je rađen pod rukovodstvom dr Dušana Sladića, kome sam zahvalna na ukazanom poverenju i pomoći pri izradi ovog rada.Veliku zahvalnost izražavam dr Zoranu Vujčiću za stalno zanimanje za moj rad, ne samo pri izradi ove disertacije već od samog početka mog naučno-istraživačkog rada.Zahvaljujem se i dr Goranu Rogliću i dr Slađani Kostić-Rajačić na podršci, pomoći i korisnim savetima tokom izrade ovog rada.Posebnu zahvalnost dugujem dr Miroslavi Vujčić za osmišljavanje eksperimenata i načina modifikacije DNA kao i izradu agaroznih gelova. Bez njene pomoći i zalaganja, proučavanje mehanizma dejstva hinonskih jedinjenja bilo bi mnogo komplikovanije.Zahvaljujem se i svim kolegama iz laboratorije. Oni su bili uz mene i kada je igranje hemijom bilo zabavno ali i kada me je trebalo preživeti.Zahvalna sam i svim ostalim kolegama, koji zbog moje nespretnosti nisu stali u ovu zahvalnicu, a koji su doprineli da mi naučno-istraživački dani budu veseliji i ispunjeniji.Zahvalnost dugujem i suprugu Miroslavu i sinu Dimitriju na bezrezervnoj podršci.Ovu doktorsku disertaciju posvećujem mojoj nani. Sigurna sam da bi ona prokomentarisala: "Ja sam za tebe životno školovani Bizmark a ti si sada zvanično školovana baraba!" ali sam isto tako sigurna da bi se beskrajno radovala sa mnom. ii Doktorska disertacijaProučavanje interakcija biološki aktivnog hinona avarona i njegovih derivata sa lizozimom, linearnom i cirkularnom dezoksiribonukleinskom kiselinom IZVOD Cilj našeg rada bio je ispitivanje biološke aktivnosti metilamino-i metoksiderivata avarona i razjašnjavanje mehanizma njihovog biološkog dejstva.Za sintezu su izabrani derivati za koje se očekivalo da će imati negativniji polutalasni potencijal od avarona i samim tim pokazivati povećanu aktivnost. Sintetisani SUMMARYThe aim of our work has been investigation of biological activity of methylamino-and metoxy-derivatives of avarone, their bioconjugates of lysozyme and study of the mechanism of their biological action.For synthesis were chosen derivatives for which it was expected to have more negative half-wave potential than avarone and therefore a higher activity. The selected compounds are 3'-methylamino, 4'-methylamino-and 3'-methoxyavarone.Antimicrobial activity of the synthesized derivatives was investigated towards The mechanism of action of avarone and its derivatives on circular plasmids pRB322 and pUC18 DNA and their action on DNA of bovine thymus was investigated as well. UV spectra of plasmid and bovine thymus DNA and their modifications were recorded and interactions with quinones were studied by electrophoresis on agarose gel.

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Few constraints limit the design of quinone methide-oligonucleotide self-adducts for directing DNA alkylation

Cited by 31 publications

References 23 publications

Inducible Alkylation of DNA by a Quinone Methide–Peptide Nucleic Acid Conjugate

Inducible Alkylation of DNA by a Quinone Methide–Peptide Nucleic Acid Conjugate

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

Investigation of interactions of biologically active quinone avarone and its derivates with lysozyme, linear and circular deoxyribonucleic acid

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