The Cytotoxicity of Duocarmycin Analogues is Mediated through Alkylation of DNA, not Aldehyde Dehydrogenase 1: A Comment

Tercel, Moana; McManaway, Sarah; Leung, Euphemia; Liyanage, H.D. Sarath; Lü, Guo-Liang; Pruijn, Frederik B.

doi:10.1002/anie.201208373

Cited by 24 publications

(18 citation statements)

References 24 publications

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“…These distances are considered to be too long to allow effective DNA alkylation to occur. Additionally, the angles of N3‐C9‐C8b for 9 R were positioned in an inefficient orientation (62° and 77°) . Thus, the ICL activity of conjugate 7 , which bears the racemic form of the seco ‐CBI moiety, was weaker than that of conjugate 6 .…”

Section: Methodsmentioning

confidence: 83%

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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: 83%

“…Compared with the CPI, the seco ‐CBI moiety has greater reactivity and selectivity toward DNA and is more stable in aqueous solution . The seco ‐CBI dimer can form DNA ICLs in the cell nucleus and exert extreme cytotoxicity to cancer cell lines …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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“…Their molecular structure shows an indole moiety as DNA-binding component and a spirocyclopropylcyclohexadienone moiety as pharmacophore group that causes sequence-selective DNA alkylation (23). A recent controversial theory claims that duocarmycins act also by inhibiting aldehyde dehydrogenase 1, an enzyme target that plays important roles in the viability and detoxification of cancer cells (24)(25)(26). For ADCs applications, we have used duocarmycin analogues that had previously been shown to be more potent and more synthetically accessible than their naturally occurring counterpart (27).…”

Section: Introductionmentioning

confidence: 99%

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

et al. 2014

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It is generally thought that the anticancer efficacy of antibody-drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569-78. Ó2014 AACR.

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“…The effect of the alkyne tag of 19 on DNA binding and alkylation was investigated by studying the reactions of 8 and 19 with ctDNA, in a similar manner to our previous characterisation of 4, and the formation of related adenine adducts (those of aminoCI [3e] and a phenolCBI dimer [16] ). Both compounds were incubated with a 250-fold base pair excess of ctDNA, and samples were taken at intervals and the DNA precipitated.…”

Section: Biological Properties Of 18 and 19mentioning

confidence: 99%

“…These same optimised conditions were used in our recent study to show nuclear localisation of a phenolic CBI alkyne. [16] Click detection following hypoxia-selective nitroCBI activation…”

Section: Flow Cytometrymentioning

confidence: 99%

Preparation and Properties of Clickable Amino Analogues of the Duocarmycins: Factors That Affect the Efficiency of Their Fluorescent Labelling of DNA

et al. 2014

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Herein we report the synthesis of three DNA-alkylating amino analogues of the duocarmycins that carry an alkyne functional group suitable for copper-catalysed click chemistry. The alkyne-containing substituents are connected via a side chain position which projects away from the minor groove, and have only a small effect on DNA alkylation and cytotoxicity. The efficiency of click reactions with fluorophore azides was studied using alkylated ctDNA by analysing the adenine adducts produced after thermal depurination. Click reactions "on DNA" were sensitive to steric effects (tether length to the alkyne) and, surprisingly, to the nature of the fluorophore azide. With the best combination of click partners and reagents, adducts could be detected in the nuclei of treated cells by microscopy or flow cytometry, provided that an appropriate detergent (Triton X-100 and not Tween 20) was used for permeabilisation. The method is sensitive enough to detect adducts at physiologically relevant concentrations, and could have application in the development of nitro analogues of the duocarmycins as hypoxia-activated anticancer prodrugs.

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The Cytotoxicity of Duocarmycin Analogues is Mediated through Alkylation of DNA, not Aldehyde Dehydrogenase 1: A Comment

Cited by 24 publications

References 24 publications

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

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

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

Preparation and Properties of Clickable Amino Analogues of the Duocarmycins: Factors That Affect the Efficiency of Their Fluorescent Labelling of DNA

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