The chemistry, mechanism of action and biological properties of CC-1065, a potent antitumor antibiotic.

Reynolds, Vincent L.; McGovren, J. Patrick; Hurley, Laurence H.

doi:10.7164/antibiotics.39.319

Cited by 120 publications

(105 citation statements)

References 28 publications

(9 reference statements)

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“…Melting temperature studies have shown that these bulky base adducts alter the thermodynamic characteristics of DNA in different ways. AAF adducts (14,15), BPDE adducts (16,17) and UV radiation products (18) destabilize the DNA double helix relative to nonmodified DNA, whereas 8-MOP (19,20), anthramycin (21), and CC-1065 adducts (22) stabilize the DNA duplex. In the predominant adduct formed by N-acetoxy-2-acetylaminofluorene (AAF-C 8 -guanine), the modified base is rotated out of the helix axis, and the duplex is locally denatured (14,23).…”

Section: Nucleotide Excision Repair (Ner)mentioning

confidence: 99%

Recognition of DNA Adducts by Human Nucleotide Excision Repair

Gunz

Heß

Naegeli

1996

Journal of Biological Chemistry

187

147

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The mechanism by which mammalian nucleotide excision repair (NER) detects a wide range of base lesions is poorly understood. Here, we tested the ability of human NER to recognize bulky modifications that either destabilize the DNA double helix (acetylaminofluorene (AAF) and benzo[a]pyrene diol-epoxide (BPDE) adducts, UV radiation products) or induce opposite effects by stabilizing the double helix (8-methoxypsoralen (8-MOP), anthramycin, and CC-1065 adducts). We constructed plasmid DNA carrying a defined number of each of these adducts and determined their potential to sequester NER factors contained in a human cell-free extract. For that purpose, we measured the capacity of damaged plasmids to compete with excision repair of a site-directed NER substrate. This novel approach showed differences of more than 3 orders of magnitude in the efficiency by which helix-destabilizing and helixstabilizing adducts sequester NER factors. For example, AAF modifications were able to compete with the NER substrate ϳ1740 times more effectively than 8-MOP adducts. The sequestration potency decreased with the following order of adducts, AAF > UV BPDE > 8-MOP > anthramycin, CC-1065. A strong preference for helix-destabilizing lesions was confirmed by monitoring the formation of NER patches at site-specific adducts with either AAF or CC-1065. This comparison based on factor sequestration and repair synthesis indicates that human NER is primarily targeted to sites at which the secondary structure of DNA is destabilized. Thus, an early step of DNA damage recognition involves thermodynamic probing of the duplex. Nucleotide excision repair (NER)1 is an essential pathway for removing bulky base modifications from DNA. This repair mechanism involves endonucleolytic cleavage at two phosphodiester bonds, one 3Ј and the other 5Ј of the site of damage, followed by excision of DNA damage as the component of a single-stranded fragment (1-5). The excised oligonucleotide is replaced by DNA repair synthesis, and DNA continuity is reestablished by ligation. In mammalian cells, the major sites of incision are at the 5th phosphodiester bond 3Ј and the 24th phosphodiester bond 5Ј to the lesion (6).

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Section: Nucleotide Excision Repair (Ner)mentioning

confidence: 99%

Recognition of DNA Adducts by Human Nucleotide Excision Repair

Gunz

Heß

Naegeli

1996

Journal of Biological Chemistry

187

147

View full text Add to dashboard Cite

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“…11) (along with more recent duocarmycin derivatives) is among the most potent antitumor agents discovered to date [86][87][88][89][90][91]. Strictly speaking, CC-1065 is not a QM, but the cyclopropane moiety present on its structure is, from a reactivity point of view, a bioisosteric form of the methide found in QMs.…”

Section: Modulation Of Qm Reactivity Towards Nuc-leophiles Drugs Withmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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“…Indeed, previous biochemical studies (56) using human cell extracts showed that CC-1065 adducts were relatively poorly incised in vitro when compared with major groove lesions such as those produced by acetylaminofluorene and UV light. Two possible explanations presented for this were the relatively low level of DNA structural distortion induced by CC-1065 adducts and/or thermodynamic stabilization of the double helix by these adducts (64). Studies in mammalian cells also revealed the importance of transcription-coupled NER in the repair of AS-I-145 -induced damage.…”

Section: Discussionmentioning

confidence: 99%

DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

Kiakos

Sato

Asao

et al. 2007

Molecular Cancer Therapeutics

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AS-I-145 is a novel achiral seco-amino-cyclopropylbenz[e]indolone (seco-amino-CBI) analogue of duocarmycin that has evolved from an alternative strategy of designing CC-1065/duocarmycin agents lacking the characteristic chiral center of the natural agents. The sequence specificity of this compound was assessed by a Taq polymerase stop assay, identifying the sites of covalent modification on plasmid DNA. The adenine-N3 adducts were confirmed at AT-rich sequences using a thermally induced strand cleavage assay. These studies reveal that this compound retains the inherent sequence selectivity of the related natural compounds. The AS-

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The chemistry, mechanism of action and biological properties of CC-1065, a potent antitumor antibiotic.

Cited by 120 publications

References 28 publications

Recognition of DNA Adducts by Human Nucleotide Excision Repair

Recognition of DNA Adducts by Human Nucleotide Excision Repair

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

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