Interstrand DNA cross-linking with dimers of the spirocyclopropyl alkylating moiety of CC-1065

Mitchell, Mark A.; Johnson, Paul D.; Williams, Marta G.; Aristoff, Paul A.

doi:10.1021/ja00198a068

Cited by 42 publications

(11 citation statements)

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“…To reduce the side effects and to increase selectivity, many new types of crosslinking agents have been investigated extensively . A member of the cyclopropapyrroloindole (CPI) family, bizelesin (NSC‐615 291) is a bifunctional alkylating agent that contains two alkylating CPIs linked by a flexible methylene chain . Based on its preference for AT‐rich sequences and its antitumor activity, the National Cancer Institute has selected bizelesin as a potential chemotherapeutic agent .…”

Section: Methodsmentioning

confidence: 99%

“…[5] Am ember of the cyclopropapyrroloindole (CPI) family,b izelesin (NSC-615291)i sabifunctional alkylating agent that contains two alkylating CPIs linked by aflexible methylene chain. [6] Based on itsp reference for AT-rich sequences and its antitumora ctivity, [7] the National Cancer Institute has selected bizelesin as ap otential chemotherapeutic agent. [8] Compared with the CPI, the seco-CBI moiety has greater reactivity and selectivity toward DNA and is more stable in aqueous solution.…”

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confidence: 99%

“…In this study,H -pin imidazole-pyrrole polyamide 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-CBI) conjugates that produce sequence-specific DNA ICLs were designed and synthesized.C onjugates with H-pin polyamide and seco-CBI moieties were constructed to recognizea7bpD NA sequence, and their reactivity and selectivity in DNA alkylation were evaluated by using high-resolution denaturing gel electrophoresis and sequence-specific plasmidc leavage. One conjugate (6), which contained ac hiral (S)-seco-CBI, exhibited greater sequence-specific ICL activity towardt he targetD NA sequence and was cytotoxic to ac ancerc ell line. Molecular modeling studies indicated that the greatera ctivity of 6 resulted from the relative orientation of the cyclopropane group in the (S)-CBI unit.…”

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DNA Interstrand Crosslinks by H‐pin Polyamide (S)‐seco‐CBI Conjugates

et al. 2016

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Although DNA interstrand crosslinking (ICL) agents are widely used as antitumor drugs, DNA sequence-specific ICL agents are quite rare. In this study, H-pin imidazole-pyrrole polyamide 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-CBI) conjugates that produce sequence-specific DNA ICLs were designed and synthesized. Conjugates with H-pin polyamide and seco-CBI moieties were constructed to recognize a 7 bp DNA sequence, and their reactivity and selectivity in DNA alkylation were evaluated by using high-resolution denaturing gel electrophoresis and sequence-specific plasmid cleavage. One conjugate (6), which contained a chiral (S)-seco-CBI, exhibited greater sequence-specific ICL activity toward the target DNA sequence and was cytotoxic to a cancer cell line. Molecular modeling studies indicated that the greater activity of 6 resulted from the relative orientation of the cyclopropane group in the (S)-CBI unit.

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Section: Methodsmentioning

confidence: 99%

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DNA Interstrand Crosslinks by H‐pin Polyamide (S)‐seco‐CBI Conjugates

et al. 2016

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“…Molecules containing two CPI groups have been developed to achieve higher potency from intra-and interstrand DNA crosslinking (Mitchell et al, 1989;Boger et al, 2000). Most notably, bizelesin, a CPI-dimer, was evaluated in a phase I clinical trial for advanced solid tumors (Schwartz et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Most notably, bizelesin, a CPI-dimer, was evaluated in a phase I clinical trial for advanced solid tumors (Schwartz et al, 2003). Mitchell et al (1989) synthesized several CPI dimers and found an optimal chain length of three carbons with a 2-pM in vitro IC 50 . Jia and Lown (2000) also reported seco-CBI dimers linked with three carbons showing the highest in vitro potency.…”

Section: Introductionmentioning

confidence: 99%

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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