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

Li, Li H.; Kelly, Robert C.; Warpehoski, Martha A.; McGovren, J. Patrick; Gebhard, I.; DeKoning, Thomas F.

doi:10.1007/bf00175081

Cited by 78 publications

(28 citation statements)

References 16 publications

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“…The first two, named U-71,184 (75) and adozelesin (U-73975, 76), 103,104 were derived from the first stage of studies on CC-1065 analogs, in which systematic simplifications of the DNA binding subunit were conducted. Adozelesin is characterized by a high potency and a promising profile of preclinical activity against murine and human tumor models, but devoid of delayed or irreversible toxicity of the parent compound.…”

Section: A Clinical Candidatesmentioning

confidence: 99%

DNA minor groove binders as potential antitumor and antimicrobial agents

Baraldi

Bovero

Fruttarolo

et al. 2004

Medicinal Research Reviews

354

222

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DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1-c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames.

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Section: A Clinical Candidatesmentioning

confidence: 99%

DNA minor groove binders as potential antitumor and antimicrobial agents

Baraldi

Bovero

Fruttarolo

et al. 2004

Medicinal Research Reviews

354

222

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“…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). 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).…”

mentioning

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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“…Adozelesin is a synthetic alkylating agent derived from the antitumor antibiotic, CC-1065 (Hanka et al, 1978;Li et al, 1991). CC-1065 and adozelesin contain a DNA-reactive cyclopropyl group that alkylates the N-3 of adenine and forms covalent adducts.…”

Section: Introductionmentioning

confidence: 99%

Mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts

2010

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Adozelesin is a synthetic analog of the antitumor antibiotic, CC-1065, which alkylates N3 of adenine in the minor DNA groove in a sequence-specific manner. Here we tested the mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts using a shuttle vector assay. Adozelesin primarily induces mutations via an A --> T transversion and a single base insertion. The A --> T transversion (43/59) was observed at the adenine alkylation site in the 5'-ATTTA* sequence (A* is the site of alkylation). The single base insertion (5/59) was observed at the 3'-side of the covalently modified adenine in the 5'-CTAAA* sequence. The results of this study suggest that the DNA alkylating sequence of adozelesin influences the type of DNA mutation.

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

Cited by 78 publications

References 16 publications

DNA minor groove binders as potential antitumor and antimicrobial agents

DNA minor groove binders as potential antitumor and antimicrobial agents

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

Mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts

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