Reaction of the Antitumor Antibiotic CC-1065 with DNA: Structure of a DNA Adduct with DNA Sequence Specificity

Hurley, Laurence H.; Reynolds, Vincent L.; Swenson, D.; Petzold, Gary L.; Scahill, T. A.

doi:10.1126/science.6494915

Cited by 220 publications

(167 citation statements)

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“…This is a new finding which increases the number of DNA lesions potentially recognized by the MMR proteins. It should be noted that, in contrast to CDDP which induces a relatively high number of drug adducts in the major groove of DNA, all the three alkylating MGB tested produced only a limited number of DNA lesions (Hurley et al, 1984;Broggini et al, 1991Broggini et al, , 1995. This is particularly true for tallimustine which is able to alkylate the N3 of adenine only when present in the hexamer sequence 5′-TTTTGA (Broggini et al, 1995).…”

Section: Discussionmentioning

confidence: 96%

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

et al. 1999

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Mismatch DNA repair deficiency is associated with resistance to certain major groove alkylating agents including methylating agents and cisplatin. We have now studied the relevance of mismatch repair alterations to the cytotoxicity induced by drugs which alkylate N3 adenines in the minor groove of DNA. We have used the mismatch repair defective human colocarcinoma cell line HCT-116 which has a mutation in the hMLH1 gene, and a subline where hMLH1 expression is restored by chromosome 3 transfer (HCT-116+ch3). We have tested three alkylating minor groove binders (tallimustine, carzelesin and CC1065) and one non-covalent minor groove binder (PNU 151807). The HCT-116+ch3 subline was more sensitive than the parental line to the treatment with the three alkylating minor groove binders, while the non-alkylating compound had a similar activity in both cell lines. Further support for mismatch repair being involved in sensitivity of the minor groove alkylators is that two cisplatin-resistant sublines of the human ovarian adenocarcinoma cell line A2780 (A2780/CP70 and A2780/MCP-1) are defective in hMLH1 expression and are more resistant to these agents than the parental mismatch repair proficient cells. Furthermore, the restoration of hMLH1 activity in the A2780/CP70 cell line, by introduction of chromosome 3, was associated with an increased sensitivity to the three alkylating minor groove binders. Again, the non-covalent minor groove binder was equally effective in mismatch repair deficient and proficient clones. The data indicate that mismatch repair deficiency mediated by loss of hMLH1 expression is associated not only with drug-resistance to major groove binders, but also to minor groove binders. However, loss of mismatch repair does not mediate resistance to the non-covalent minor groove binder PNU 151807. © 1999 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 96%

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

et al. 1999

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“…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. It binds preferentially to double-stranded B-DNA within the minor groove, with a sequence preference for 5'-d(A/GNTTA)-3' and 5'-d(AAAAA)-3', and it alkylates the N3 position of the 3'-adenine with its left-hand CPI segment [92][93].…”

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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“…The 3,3-bipyrrole was then converted through a series of reactions into the acid chloride (9) which was immediately treated with SnCl4 -CH2Cl2 at -78°C to give the tricyclic phenol (10). Selective reduction of 10 leads to the formation of the alcohol (11) which was converted by the intramolecular MITSU-NOBU reaction into the cyclopropylspirocyclo-hexadienone (12), the "A" subunit of CC-1065.…”

Section: Synthesis Of the "A" Subunitmentioning

confidence: 99%

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

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Reaction of the Antitumor Antibiotic CC-1065 with DNA: Structure of a DNA Adduct with DNA Sequence Specificity

Cited by 220 publications

References 3 publications

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents

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

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

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