Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles

Laurie L. Parker; Fiona M. Anderson; C. Caroline O'Hare; Stephen M. Lacy; John P. Bingham; David J. Robins; John A. Hartley

doi:10.1016/j.bmc.2005.01.055

Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles

Laurie L. Parker, Fiona M. Anderson, C. Caroline O'Hare, Stephen M. Lacy, John P. Bingham, David J. Robins, John A. Hartley

Biochemistry, Molecular Biology, and Biophysics (CBS)

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC ₅₀ values 6-100 μM) comparable with chlorambucil (45 μM) and melphalan (8.5 μM). In particular the cyclen derivative 2a was more than 10⁴ times more effective at cross-linking DNA (2a XL₅₀ ≪ 10 nM) than chlorambucil (XL₅₀ 100 μM), and showed significant cytotoxicity in human tumour cells in vitro.

Original language	English (US)
Pages (from-to)	2389-2395
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2005.01.055
State	Published - Apr 1 2005

Bibliographical note

Funding Information:
We thank the University of Glasgow (2001 Scholarship) and Universities UK (ORS Award) (LLP), the Association for International Cancer Research (FMA and SML) and Cancer Research UK (JAH) for funding. We acknowledge Nicholas Gowans for assisting with the synthesis of some of the compounds, as well as Anthony Ritchie and James Tweedie of the University of Glasgow for obtaining high-resolution mass spectra of the compounds.

Keywords

Anticancer
DNA cross-linking
Nitrogen mustards
Polyazamacrocycles

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2005.01.055

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abstract = "We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC 50 values 6-100 μM) comparable with chlorambucil (45 μM) and melphalan (8.5 μM). In particular the cyclen derivative 2a was more than 104 times more effective at cross-linking DNA (2a XL50 ≪ 10 nM) than chlorambucil (XL50 100 μM), and showed significant cytotoxicity in human tumour cells in vitro.",

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note = "Funding Information: We thank the University of Glasgow (2001 Scholarship) and Universities UK (ORS Award) (LLP), the Association for International Cancer Research (FMA and SML) and Cancer Research UK (JAH) for funding. We acknowledge Nicholas Gowans for assisting with the synthesis of some of the compounds, as well as Anthony Ritchie and James Tweedie of the University of Glasgow for obtaining high-resolution mass spectra of the compounds.",

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AU - Bingham, John P.

AU - Robins, David J.

AU - Hartley, John A.

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N2 - We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC 50 values 6-100 μM) comparable with chlorambucil (45 μM) and melphalan (8.5 μM). In particular the cyclen derivative 2a was more than 104 times more effective at cross-linking DNA (2a XL50 ≪ 10 nM) than chlorambucil (XL50 100 μM), and showed significant cytotoxicity in human tumour cells in vitro.

AB - We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC 50 values 6-100 μM) comparable with chlorambucil (45 μM) and melphalan (8.5 μM). In particular the cyclen derivative 2a was more than 104 times more effective at cross-linking DNA (2a XL50 ≪ 10 nM) than chlorambucil (XL50 100 μM), and showed significant cytotoxicity in human tumour cells in vitro.

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Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles

Abstract

Bibliographical note

Keywords

UN SDGs

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