Are the Duocarmycin and CC-1065 DNA Alkylation Reactions Acid-Catalyzed? Solvolysis pH−Rate Profiles Suggest They Are Not

Boger, Dale L.; Garbaccio, R. M.

doi:10.1021/jo990762g

Cited by 35 publications

(38 citation statements)

References 34 publications

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“…Amide hydrolysis represents another major degradation pathway for these chloro-seco-CPI/CBI compounds, with detection of 2c and 2d as the main products. Additionally, solvolysis product 2e was observed in relatively low quantities, likewise to a previous report (Boger and Garbaccio, 1999a).…”

Section: Resultssupporting

confidence: 86%

“…Solvolysis of the CPI/CBI compounds can be considered another degradation pathway, and the extent of degradation in acidic buffer has been used to assess the reactivity against common nucleophiles (Tercel et al, 2014). However, CPI/CBIs have been shown to be mostly inert under physicological conditions (Boger and Garbaccio, 1999a). In this study, solvolysis was minimal in buffer at pH 7.4, with only seco-CPI 2 having detectable solvolysis product 2e (Fig.…”

Section: Discussionmentioning

confidence: 60%

See 1 more Smart Citation

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

Wang¹,

Chen²,

Dragovich³

et al. 2019

Drug Metab Dispos

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Duocarmycins [including cyclopropyl pyrroloindole (CPI) or cyclopropyl benzoindole (CBI)] are a class of DNA minor-groove alkylators and seco-CPI/CBIs are synthetic pro-forms that can spirocyclize to CPI/CBI. Bis-CPI/CBIs are potential drug candidates because of their enhanced cytotoxicity from DNA crosslinking, but it is difficult to analyze them for structure-activity correlation because of their DNA reactivity. To study their DNA alkylation, neutral thermal hydrolysis has been frequently applied to process depurination. However, unwanted side reactions under this condition have been reported, which could lead to poor correlation of DNA alkylation data with efficacy results, especially for bis-CPI/CBIs. In this study, an acidic depurination method was developed and applied for analysis of DNA alkylation and shown to be an easier and milder method than the traditional neutral thermal hydrolysis. DNA alkylation and stability of three bis-seco-CBIs were characterized in comparison with two mono-seco-CPIs. The results suggested that: 1) The acidic depurination method was capable of capturing a more representative population, sometimes a different population, of DNA adducts as they existed on DNA compared with the heat depurination method. 2) Di-adenine adducts were captured as expected for the CBI dimers, although the major type of adduct was still mono-adenine adducts.3) The rate of DNA alkylation, DNA adduct profile, and relative amounts of di-adduct versus mono-adduct were significantly affected by the size, and possibly lipophilicity, of the nonalkylating part of the molecules. 4) Spirocyclization and amide hydrolysis represented two major pathways of degradation. Overall, by applying acidic depurination analyses, this study has illustrated DNA adduct characteristics of novel bis-seco-CBIs with dominating monoalkylation and provides an alternative method for evaluating DNA minor-groove alkylators. These findings provide an effective analytical tool to evaluate DNA alkylators and to study the DNA alkylation that is a disposition mechanism of these compounds. Polakis, 2016). With this as an objective, duocarmycins were made and https://doi.org/10.1124/dmd.118.085209.s This article has supplemental material available at dmd.aspetjournals.org.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 60%

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

Wang¹,

Chen²,

Dragovich³

et al. 2019

Drug Metab Dispos

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“…CBI-based analogues are synthetically more accessible than the natural products, are chemically more stable and retain potent biological activity [2,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. The CBI subunit has found significant applications in prodrug therapy and work in this area is discussed later in this review.…”

Section: 299a-tetrahydrocyclopropa[c]benz[e]indol-4-one (Cbi)mentioning

confidence: 99%

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

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CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products

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“…A large part of the work in this field has been performed by Boger and co-workers [46,[49][50][51][52][53][54][55][56][57][58][59][60][61][62], who have synthesised and examined different alkylation subunits in order to establish the steric and electronic factors necessary for reactivity. They have studied a series of natural and modified agents containing structural modifications in the alkylation subunit (4 -13) and observed an interesting correlation between the solvolytic stability of the cyclopropane ring and cytotoxicity ( In fact, the compound with the greatest solvolytic stability (pH 3) exhibits the most potent cytotoxic activity.…”

Section: Alkylating Subunitsmentioning

confidence: 99%

CC-1065 and the duocarmycins: recent developments

Cacciari

Romagnoli

Baraldi

et al. 2000

Expert Opinion on Therapeutic Patents

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It is accepted that neoplastic diseases are related to gene alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA based moieties. In this field, analogues of naturally occurring antitumour agents, such as CC-1065 and/or the duocarmycins, represent a new class of highly potent antineoplastic compounds, currently under investigation. CC-1065 and duocarmycins represent a class of exceptionally potent antitumour antibiotics that derive their biological effects from the reversible, stereoelectronically-controlled sequence selective alkylation of DNA. All natural compounds showed a cytotoxicity against leukaemia L1210 cell lines in the range 10 -220pM but while CC-1065 showed a good antitumour activity in an in vivo model (optimal dose from 10 -100 µg/g), duocarmycins showed weak antitumour activity. Despite its potency, CC-1065 cannot be used in humans due to eventual fatality. For this reason many scientists have focused their attention on this class of compounds, in order to obtain new derivatives with equal in vitro potency but a better profile in in vivo models. This effect is accompanied by dramatic changes in the morphology of hepatic mitochondria. On this basis, the recent developments on SARs for this class of compounds and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature and, finally, a conclusive opinion will be given on this topic.

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Are the Duocarmycin and CC-1065 DNA Alkylation Reactions Acid-Catalyzed? Solvolysis pH−Rate Profiles Suggest They Are Not

Cited by 35 publications

References 34 publications

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

CC-1065 and the duocarmycins: recent developments

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