Stereoelectronic factors influencing the biological activity and DNA interaction of synthetic antitumor agents modeled on CC-1065

Warpehoski, Martha A.; Gebhard, I.; Kelly, Robert C.; Krueger, William C.; Li, L. H.; McGovren, J. Patrick; Prairie, Mark D.; Wicnienski, Nancy A.; Wierenga, Wendell

doi:10.1021/jm00398a017

Cited by 130 publications

(70 citation statements)

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“…The drug has no detectable reactivity with protein (9), and DNA adduct formation by the cyclopropyl moiety of adozelesin and other members of this family of drugs is essential for the biological activity of these compounds (1). Therefore, adozelesin's inhibitory effects on initiation are likely related to formation of adozelesin-DNA adducts rather than interactions between adozelesin and DNA replication proteins or noncovalent interactions between adozelesin and DNA.…”

Section: Discussionmentioning

confidence: 99%

“…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)(3)(4)(5)(6).…”

mentioning

confidence: 99%

“…In this study, the intracellular effects of adozelesin on DNA replication were examined using simian virus 40 (SV40) 1 -infected African green monkey kidney cells (BSC-1) as a well defined DNA replication model. Except for the virally encoded large tumor antigen, SV40 DNA replication is completely dependent upon the enzymatic machinery of the host cell (26).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Similarly, the unnatural enantiomer of the reversed agent ent-(-)-CDPI2-DSA (26) was found to alkylate the same sites as (+)-DSA-CDPI2 (25) [77][78][79], and the extensive number of investigations directed at the subunits of the natural products (33), studies that have provided analogs (80,81) and agents containing deepseated structural modifications have proven unusually valuable in defining the relationships between structure, functional reactivity, and biological properties (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97). The acid-catalyzed activation of the DNA alkylation reaction led to the intuitive proposal that there may exist a direct relationship between the reactivity and cytotoxic activity of the agents and established the expectation that the biological potency may be enhanced as the electrophilic reactivity is increased (81). However, studies conducted with the agents 27-32, which were prepared by synthesis employing technology developed in the natural product total syntheses, revealed the reverse relationship and that the agents possessing the greatest stability may be expected to exhibit the most potent cytotoxic activity.…”

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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.

213

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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“…During the past several years, a great number of analogs incorporating the DNA-reactive left-hand cyclopropylpyrroloindole (CPI) moiety of CC-1065 have been prepared by total synthesis [8][9][10][11] and have been evaluated in cancer models. The highest potencies and antitumor activities were produced by analogs containing extended aromatic segments attached to the alkylative CPI moiety [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Adozelesin, a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic, CC-1065

Kelly

Warpehoski

et al. 1991

Invest New Drugs

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Adozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p. - or s.c.- implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.

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Stereoelectronic factors influencing the biological activity and DNA interaction of synthetic antitumor agents modeled on CC-1065

Cited by 130 publications

References 3 publications

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

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

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

Adozelesin, a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic, CC-1065

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