The structure of CC-1065, a potent antitumor agent and its binding to DNA

Chidester, C. G.; Krueger, William C.; Mizsak, S. A.; Duchamp, D. J.; Martin, David G.

doi:10.1021/ja00415a035

Cited by 154 publications

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“…One of the newest class of agents shown to alkylate DNA includes (+)-CC-1065 (1; ref. 19), (+)-duocarmycin A (2; refs. [20][21][22][23][24], and (+)-duocarmycin SA (3; refs.…”

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confidence: 99%

“…In the first key study (59,70,71), it was shown that 17-20 exhibited identical alkylation selectivities (5'-AA > 5'-TA) independent of their absolute configuration and identical to both enantiomers of 11 and 12. In addition, the natural enantiomers of [21][22][23][24] exhibited DNA alkylation selectivities identical to that of (+)-CC-1065 and were more selective and more efficient than [17][18][19][20] ,.-OMs (43). One unique feature of 3 is the C6 methyl ester on the left-hand side of the alkylation subunit that complements the right-hand side linking amide.…”

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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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“…One of the newest class of agents shown to alkylate DNA includes (+)-CC-1065 (1; ref. 19), (+)-duocarmycin A (2; refs. [20][21][22][23][24], and (+)-duocarmycin SA (3; refs.…”

mentioning

confidence: 99%

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confidence: 99%

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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“…1, adozelesin is composed of three heterocyclic subunits linked serially by amide bonds. Similar to the parent compound, CC-1065, this structure conforms to the curved shape of DNA by mimicking the twist of the helix and allowing the drug to bind within the minor groove in a sequence-specific manner (11)(12)(13)(14)(15)(16). The indole and benzofuran substituents of adozelesin (Fig.…”

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confidence: 99%

Inhibition of Initiation of Simian Virus 40 DNA Replication in Infected BSC-1 Cells by the DNA Alkylating Drug Adozelesin

Cobuzzi

Burhans

Beerman

1996

Journal of Biological Chemistry

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Adozelesin is a member of a family of extraordinarily cytotoxic DNA damaging agents that bind to the DNA minor groove in a sequence-specific manner and form covalent adducts with adenines. Previous studies employing purified enzymes and adozelesin-modified template DNAs suggested that adozelesin-DNA adducts inhibit DNA replication at the level of nascent DNA chain elongation. In this study, neutral/neutral two-dimensional agarose gel electrophoresis was employed to analyze simian virus 40 (SV40) DNA replication intermediates recovered from adozelesin-treated SV40 virusinfected cells. SV40 replication intermediates rapidly disappeared from infected cells when they were treated with adozelesin, but not when the cells were also treated with aphidicolin to block maturation of replicating SV40 DNA. We conclude that the disappearance of SV40 replication intermediates induced by adozelesin treatment was a consequence of maturation of these intermediates in the absence of new initiation events. Adozelesin inhibition of nascent chain elongation is first observed at concentrations above those needed to block initiation. Adozelesin treatment inhibits SV40 DNA replication at concentrations that produce adducts on just a small fraction of the intracellular population of SV40 DNA molecules.Adozelesin (U-73,975) is a synthetic analog of the antitumor antibiotic CC-1065 (1). The cytotoxic activity of adozelesin is orders of magnitude more potent than many common antineoplastic agents such as doxorubicin, cisplatin, 5-fluorouracil, or cytosine arabinoside (2-6). It is highly effective against a broad spectrum of murine tumors and human tumor xenografts without the lethal hepatotoxicity caused by CC-1065 (7). Adozelesin was chosen for clinical development based upon this in vivo potency and efficacy, and is currently undergoing phase II clinical evaluation (8).A primary intracellular target of adozelesin is DNA (3, 9). Like CC-1065, adozelesin elicits its potent cytotoxic and antitumor effects by alkylating DNA (10). As shown in Fig. 1, adozelesin is composed of three heterocyclic subunits linked serially by amide bonds. Similar to the parent compound, CC-1065, this structure conforms to the curved shape of DNA by mimicking the twist of the helix and allowing the drug to bind within the minor groove in a sequence-specific manner (11-16). The indole and benzofuran substituents of adozelesin (Fig. 1, subunits B and C, respectively) form non-covalent interactions with DNA that may contribute to the sequence preference of the drug (11,(17)(18)(19)(20)(21)(22). These non-covalent interactions cause bending and stiffening of the DNA helix (11-13). After binding to the minor groove, the cyclopropyl ring of the left-hand cyclopropylpyrroloindole substituent (Fig. 1) forms a covalent bond with N-3 of adenine at the 3Ј end of the binding site (23, 24). Two consensus sequences have been identified for this alkylation event: 5Ј-(A/T)(A/T)A* and 5Ј-(A/T)(G/C)(A/T)A*, where A* is the alkylated 3Ј adenine (9,22).Inhibition of DNA synthesis as ...

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“…1, structure 1) possesses potent in vitro cytotoxic activity, broad spectrum antimicrobial activity, and in vivo antitumor activity (12)(13)(14)(15)(16). In a series of investigations, the site and mechanism of the (+)-CC-1065 activity have been related to its sequence-selective minor groove alkylation of double-stranded DNA within 5-base-pair A+T-rich sequences that has been demonstrated to proceed by 3'-adenine N-3 alkylation ofthe reactive cyclopropane present in the left-hand subunit (17).…”

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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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The structure of CC-1065, a potent antitumor agent and its binding to DNA

Cited by 154 publications

References 0 publications

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

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

Inhibition of Initiation of Simian Virus 40 DNA Replication in Infected BSC-1 Cells by the DNA Alkylating Drug Adozelesin

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

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