Investigation of Reactivity and Selectivity of DNA‐Alkylating Duocarmycin Analogues by High‐Resolution Mass Spectrometry

Tietze, Lutz F.; Krewer, Birgit; Frauendorf, Holm; Major, F.; Schuberth, Ingrid

doi:10.1002/anie.200600935

Cited by 28 publications

(18 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[11a, 15b,23] Future work will aim at determining the nature of colibactin-DNA interactions using MS and CD-based techniques. [26] The current study is also proof of principle that alternative prodrug activation manifolds can be used to elicit DNA damage.Whilst this work provides acompelling link between molecular structure and cellular genotoxicity,t he story of colibactin is far from complete.Unresolved areas of question include the transportation of colibactin between producer and host, the exact mechanism of DNAc rosslinking,t he role it plays in gastrointestinal disorders and, indeed, the complete structure of colibactin itself.T oa nswer these questions am ultidisciplinary approach will be required to which preparative organic chemistry can make avaluable contribution. Figure 5.…”

Section: Zuschriftenmentioning

confidence: 54%

“…[24d, e] Our crosslinking and cellular localization studies provide strong evidence that activated colibactin molecules 7 and 9, featuring the lactam warhead, directly target nuclear DNA. [26] The current study is also proof of principle that alternative prodrug activation manifolds can be used to elicit DNA damage.Whilst this work provides acompelling link between molecular structure and cellular genotoxicity,t he story of colibactin is far from complete.Unresolved areas of question include the transportation of colibactin between producer and host, the exact mechanism of DNAc rosslinking,t he role it plays in gastrointestinal disorders and, indeed, the complete structure of colibactin itself.T oa nswer these questions am ultidisciplinary approach will be required to which preparative organic chemistry can make avaluable contribution. We note that, given its low potencyand lack of more complex structural features resulting from the full complement of biosynthetic genes in the pks cluster, compound 6 is not responsible for genotoxicity induced by pks + bacteria.…”

mentioning

confidence: 54%

See 1 more Smart Citation

Photoactivated Colibactin Probes Induce Cellular DNA Damage

et al. 2018

View full text Add to dashboard Cite

Colibactin is as mall molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks + bacteria induce agenotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in abenign, prodrug form which,p rior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif,w hich is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity,as eries of photolabile colibactin probes were prepared that upon irradiation induced apks + like phenotype in HeLa cells.Furthermore,results from DNAcross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

show abstract

Section: Zuschriftenmentioning

confidence: 54%

mentioning

confidence: 54%

Photoactivated Colibactin Probes Induce Cellular DNA Damage

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Taking into account these premises, we developed a series of second‐generation prodrugs as 3 , which can be activated by the enzyme β‐ d ‐galactosidase to give the corresponding drugs such as 4 (Figure 3) (12,13). These drugs are analogs of the highly cytotoxic natural antibiotics CC‐1065 ( 6 ) (30) and the duocarmycins [e.g., duocarmycin SA ( 5 ) (31)] and exert their cytotoxic action presumably through a sequence‐selective alkylation of double‐stranded DNA (32,33).…”

Section: First‐ and Second‐generation Prodrugsmentioning

confidence: 99%

Antibody‐Directed Enzyme Prodrug Therapy: A Promising Approach for a Selective Treatment of Cancer Based on Prodrugs and Monoclonal Antibodies

Tietze¹,

Krewer

2009

Chem Biol Drug Des

Self Cite

View full text Add to dashboard Cite

The antibody-directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non-toxic prodrugs in cancerous tissue by targeted antibody-enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC-1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., b-D-galactosidase). Furthermore, the drugs show very high cytotoxicities with IC 50 values of as low as 4.5 pM. In this report, we summarize our recent results on the development and biological evaluation of these novel third-generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.

show abstract

“…Second, the time-dependent DNA alkylation efficiency and the sequence selectivity of prodrug 1 and of its corresponding seco -drug 2 were investigated using HPLC followed by MS as well as by means of direct electrospray ionisation (ESI)–Fourier transform ion cyclotron resonance (FTICR)–MS. A short communication of parts of this work, namely the use of direct ESI–FTICR–MS for the investigation of the alkylation reaction, has recently been published [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Investigation of the transformations of a novel anti-cancer agent combining HPLC, HPLC–MS and direct ESI–HRMS analyses

2009

Self Cite

View full text Add to dashboard Cite

One of the main problems of anti-cancer therapy is an insufficient differentiation between normal and malignant cells by the known anti-proliferant agents. The antibody-directed enzyme prodrug therapy is a promising approach for a selective treatment of cancer, in which a non-toxic prodrug is enzymatically converted into a highly cytotoxic drug at the surface of malignant cells by a targeted antibody-enzyme conjugate. The transformations and the stability of a very promising novel prodrug and its corresponding cytotoxic derivative were now investigated in detail by high-performance liquid chromatography (HPLC)-mass spectrometry (MS). In order to determine the time-dependent DNA alkylation efficiency and the sequence selectivity of the novel compounds, DNA binding studies using direct electrospray-Fourier transform ion cyclotron resonance-MS (ESI-FTICR-MS) have been performed. These measurements were accompanied by HPLC analyses followed by MS of the separated species to confirm the results of the direct ESI-FTICR-MS measurements. The sites of DNA alkylation could be identified unambiguously by the mass spectrometric fragmentation pattern of the alkylated oligodeoxynucleotides as well as by the results of HPLC followed by MS. A combination of all techniques applied led to a better understanding of the mode of action of the new therapeutics and might be used for an estimation of the cytotoxicity of different prodrugs and drugs since the alkylation efficiency correlates with the bioactivity of the compounds in cell culture investigations.

show abstract

Investigation of Reactivity and Selectivity of DNA‐Alkylating Duocarmycin Analogues by High‐Resolution Mass Spectrometry

Cited by 28 publications

References 37 publications

Photoactivated Colibactin Probes Induce Cellular DNA Damage

Photoactivated Colibactin Probes Induce Cellular DNA Damage

Antibody‐Directed Enzyme Prodrug Therapy: A Promising Approach for a Selective Treatment of Cancer Based on Prodrugs and Monoclonal Antibodies

Investigation of the transformations of a novel anti-cancer agent combining HPLC, HPLC–MS and direct ESI–HRMS analyses

Contact Info

Product

Resources

About