CC-1065(NSC 298223), a potent new antitumor agent. Improved production and isolation, characterization and antitumor activity.

Martin, David G.; Biles, C.; Gerpheide, S. A.; Hanka, L. J.; Krueger, William C.; McGovren, J. Patrick; Mizsak, S. A.; Neil, Gary L.; Stewart, Julianna C.; Visser, Jeronimo

doi:10.7164/antibiotics.34.1119

Cited by 141 publications

(100 citation statements)

References 5 publications

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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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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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“…The initial limited studies conducted with naturally derived duo- carmycin SA (3), the most recent addition to this class of agents, revealed a combination of properties that make it the most exciting of the natural products identified to date. In addition to lacking the characteristic of delayed toxicity of ( + )-CCBorn August 22,1953 …”

Section: Reviewsmentioning

confidence: 99%

CC‐1065 and the Duocarmycins: Understanding their Biological Function through Mechanistic Studies

Boger

Johnson

1996

Angew. Chem. Int. Ed. Engl.

328

279

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Merely reversing the amangelnetit ot the DNA-binding atructural elements ( D S A -C D P l 2~C D P I 2 -D S A )c a~i x h a DNA alkylating agent to behabe like the enailtiornet-ofthe natural product. although the alkylation unit has the contifuration lound in nature. Model studies on the binding of the enantiorners to DNA provide an explanation. We review here studies defining the DNA alkylation properties of a class of potent antitumor antibiotics that includes CC-1065 and the duocarmycins, as well as investigations that delineate fundamental relationships between their structure, functional reactivity, and biological properties. In conjunction with the study of the natural products themselves, the examination of synthetic agents containing deep-seated structural changes, the unnatural enantiomers of the natural products, and related analogs has defined the structural basis for the sequence selective alkylation of duplex DNA and proved to be the key to understanding the fundamental relationships between chemical structure, functional reactivity, and biological properties. The characteristic DNA alkylation proceeds by reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within AT-rich minor groove sites. Both the natural and unnatural enantiomers alkylate DNA, and the sequence selectivity of both is controlled and dominated by the preferential noncovalent binding of the agents within the narrower, deeper, AT-rich minor groove and the steric accessibility to the alkylation site on penetration of this groove. Among the fundamental relationships between structure and properties, the most striking is the direct relationship between chemical or functional stability and biological potency. Within a short time, simplified and readily accessible synthetic agents rationally based on the natural product leads have been developed, which exhibit comparable and exceptional biological potency (IC50 = 50 to 51 PM) and improved efficacy. The fundamental relationships that have been defined to date can be expected to provide the foundation for future developments and advances.

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“…17,18 Studies on the mechanism of cytotoxic action have shown that CC-1065 affords its biological activity through binding to double-stranded B-DNA within the minor groove at AT-rich sequences and selectively alkylating at the N 3 position of the 3'-adenine by its cyclopropylindole (CPI) subunit 12. 19 Despite its high potency and broad spectrum of antitumor activity, CC-1065 cannot be used in humans because it causes delayed death in experimental models.…”

Section: Cpi-distamycin a Hybridsmentioning

confidence: 99%

Hybrid molecules based on distamycin A as potential antitumor agents

Baraldi¹,

Zaid²,

Preti³

et al. 2005

Arkivoc

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Many natural and synthetic anticancer agents with the ability to interact with DNA have been discovered, but most of them have relatively low therapeutic index. This is probably related to the fact that these derivatives cause DNA damage in an unspecific manner, inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. For these reasons, there has been considerable interest in finding small molecules able to alkylate the DNA with a much higher degree of sequence specificity and to modify the function of nucleic acids irreversibly. Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researcher's attention not only for the biological activity, but also for its non intercalative binding to the minor groove of doublestranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has also been used as DNA sequence selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself. The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame.

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CC-1065(NSC 298223), a potent new antitumor agent. Improved production and isolation, characterization and antitumor activity.

Cited by 141 publications

References 5 publications

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

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

CC‐1065 and the Duocarmycins: Understanding their Biological Function through Mechanistic Studies

Hybrid molecules based on distamycin A as potential antitumor agents

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