Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogs

Hurley, Laurence H.; Warpehoski, Martha A.; Lee, Chong Soon; McGovren, J. Patrick; Scahill, Terrence A.; Kelly, Robert C.; Mitchell, Mark A.; Wicnienski, Nancy A.; Gebhard, I.

doi:10.1021/ja00168a003

Cited by 115 publications

(78 citation statements)

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“…Although the results presented in Fig. 3 deviate from the two generalized consensus sequences, a strict requirement for the first 3 bases to be A or T always is observed and the final 2 base pairs are predominantly A or T (27,29). Among the features that have been suggested to contribute to minor groove binding selectivity, two general structural characteristics ofa run ofA-T base pairs may prove to be of particular importance to agents that rely principally or exclusively on stabilizing van der Waals contacts and hydrophobic binding for noncovalent binding stabilization.…”

Section: Results (+)-N-boc-cpi (+)-N-acetyl-cpi and (+)-Cc-1065mentioning

confidence: 57%

Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

Boger

Zarrinmayeh

Munk

et al. 1991

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

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Studies on the structural origin of the DNA alkylation selectivity of the antitumor antibiotic (+)-CC-1065 are detailed. The sites of alkylation of double-stranded DNA were examined for simple derivatives of 7-methyl-1,2,8,8a- The CI subunit of the agents is a much more reactive alkylating agent than the natural CPI alkylation subunit of CC-1065. Consequently, simple derivatives of CI were found to alkylate double-stranded DNA under milder conditions than were simple derivatives of CPI, and the marked similarities in the CI and CPI DNA alkylation profiles illustrate that CI represents the minimum pharmacophore of CPI. Comparisons of the DNA alkylation profiles of (+)-N-butyloxycarbonyl-CPI, (+)-N-aetyl-CPI, and (+)-CC-1065 revealed distinctions in the CPI and (+)-CC-1065 sites of alkylation, whereas the incorporation of the reactive CI electrophile into an analog of CC-1065 (CI-CDPI2) (CDPI, N3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-elindole-7-carboxylic acid) provided an agent that possesses the characteristic CC-1065 DNA alkylation profile (site selectivity and relative site intensity). These observations suggest that the noncovalent binding selectivity of the agents may restrict the number of available DNA alkylation sites and play a productive role in controlling the sequence-selective alkylation by effectively delivering the electrophile to A+T-rich minor groove regons of DNA possessing accessible adenine N-3 alkylation sites. In turn, the noncovalent binding selectivity may be derived from preferential binding within the narrower, sterically more accessible A+T-rich minor groove of double-stranded DNA.

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Section: Results (+)-N-boc-cpi (+)-N-acetyl-cpi and (+)-Cc-1065mentioning

confidence: 57%

Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

Boger

Zarrinmayeh

Munk

et al. 1991

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

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“…The study of (+)-CC-1065 revealed a similar, but more extended, 5-bp AT-rich alkylation selectivity (42,(53)(54)(55)(56)(57)(58)(59) (42,58).…”

mentioning

confidence: 90%

“…The event, sequence selectivity, quantitation, reversibility, and structure determination of the predominant DNA alkylation reaction by 1-3 have been defined (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). The alkylation site identification and the assessment of relative selectivity were derived through thermally induced depurination and strand cleavage of labeled DNA after exposure to the agents (Scheme I).…”

mentioning

confidence: 99%

“…One of the more revealing discoveries made possible through use of synthetic materials was that the unnatural enantiomers also constitute effective DNA alkylating agents (42,43,56,58). ent-(-)-Duocarmycin SA (3) was found to alkylate DNA but at concentrations -1OX that required for the natural enantiomer (43) and Table 1 summarizes its consensus alkylation sequence.…”

mentioning

confidence: 99%

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CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Boger

Johnson

1995

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

214

100

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Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronicaily controlled adenine-N3

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“…CPI drugs are currently in clinical trials for several types of solid tumors (1,2). The CPI drug, adozelesin, carries a single cyclopropyl group and alkylates a single adenine (3)(4)(5)(6). CPI adduct formation on naked DNA is able to block progression of DNA polymerases and helicases (7)(8)(9).…”

mentioning

confidence: 99%

Adozelesin Triggers DNA Damage Response Pathways and Arrests SV40 DNA Replication through Replication Protein A Inactivation

Liu

Kuo

McHugh

et al. 2000

Journal of Biological Chemistry

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The cyclopropylpyrroloindole anti-cancer drug, adozelesin, binds to and alkylates DNA. Treatment of human cells with low levels of adozelesin results in potent inhibition of both cellular and simian virus 40 (SV40) DNA replication. Extracts were prepared from adozelesintreated cells and shown to be deficient in their ability to support SV40 DNA replication in vitro. This effect on in vitro DNA replication was dependent on both the concentration of adozelesin used and the time of treatment but was not due to the presence of adozelesin in the in vitro assay. Adozelesin treatment of cells was shown to result in the following: induction of p53 protein levels, hyperphosphorylation of replication protein A (RPA), and disruption of the p53-RPA complex (but not disruption of the RPA-cdc2 complex), indicating that adozelesin treatment triggers cellular DNA damage response pathways. Interestingly, in vitro DNA replication could be rescued in extracts from adozelesin-treated cells by the addition of exogenous RPA. Therefore, whereas adozelesin and other anti-cancer therapeutics trigger common DNA damage response markers, adozelesin causes DNA replication arrest through a unique mechanism. The S phase checkpoint response triggered by adozelesin acts by inactivating RPA in some function essential for SV40 DNA replication.The cyclopropylpyrroloindole (CPI) 1 drugs are a group of DNA sequence-specific minor groove binders that alkylate the N-3 of adenine at the 3Ј end of the binding sites. CPI drugs are currently in clinical trials for several types of solid tumors (1, 2). The CPI drug, adozelesin, carries a single cyclopropyl group and alkylates a single adenine (3-6). CPI adduct formation on naked DNA is able to block progression of DNA polymerases and helicases (7-9). Previous studies have shown that two different CPI drugs, adozelesin and bizelesin, inhibit both the initiation and elongation stages of cellular and viral DNA replication in cultured cells (10 -12). However, the concentrations of these drugs required to cause S phase arrest are 2-4 orders of magnitude lower than levels of drug required to cause detectable adducts and to block polymerase or helicase progression. These results suggest that inhibition of DNA replication and cell cycle progression in cultured cells upon treatment with CPI drugs occurs via a trans-acting mechanism rather than by directly blocking DNA replication fork progression. The most likely explanation for this trans-inhibition of DNA replication is through cellular DNA damage response pathways or checkpoints.Since both viral, simian virus 40 (SV40), and cellular DNA replication are inhibited at similar CPI levels, it is possible to use the more easily studied viral system to elucidate how CPI treatment results in DNA replication arrest. SV40 DNA replication is the most well studied model for eukaryotic DNA replication. An in vitro system was developed that requires only one viral protein, SV40 large T antigen, an exogenous plasmid DNA template containing the SV40 origin sequence, and primate...

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Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogs

Cited by 115 publications

References 0 publications

Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Adozelesin Triggers DNA Damage Response Pathways and Arrests SV40 DNA Replication through Replication Protein A Inactivation

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