Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards

Atwell, Graham J.; Yaghi, Basma; Turner, Paul; Boyd, Michal; O’Connor, Charmian J.; Ferguson, Lynnette R.; Baguley, Bruce C.; Denny, William A.

doi:10.1016/0968-0896(95)00049-m

Cited by 23 publications

(18 citation statements)

References 23 publications

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“…Nevertheless, both MALDI and ESI spectra are found to include adventitious alkali metal ion adducts. The aniline mustards alkamin, molecular weight 714.6, and alkamini, molecular weight 609.0, were synthesized as the dihydrochloride salts as described previously (Prakash et al, 1991: Atwell et al, 1995. All ligands were dissolved to a concentration of 2.0 mM in a mixture of isopropanol and acetonitrile (APS Finechem), to prevent hydrolysis and loss of functional groups and stored at Ϫ20°C.…”

Section: Methodsmentioning

confidence: 99%

“…In these assays, alkamini is 35-fold less cytotoxic and lacks in vivo activity, pointing to the importance of alkamin cross-links as a major determinant of its biological activity (Atwell et al, 1995). As a reference, the clinically used alkylating agent chlorambucil, which reacts virtually exclusively at guanine N7 sites on DNA (Mattes et al, 1986a), has an IC 50 of 6.75 M against P388 leukemia, and the same in vivo efficacy as alkamin but at 25-fold higher doses (Atwell et al, 1995).…”

mentioning

confidence: 99%

“…In an attempt to maximize cross-link frequencies at sequences such as AATT and AAATTT, Denny and colleagues (Prakash et al, 1991;Atwell et al, 1995) synthesized ligands that incorporate single-armed mustard groups disposed at either end of a terephthalic acid framework (Fig. 1), the intent being to alkylate adenines four residues apart in complementary strands.…”

mentioning

confidence: 99%

“…1), binds to AT tracts in a manner consistent with these design principles (Prakash et al, 1991;Turner et al, 1999) and that its monofunctional analog, alkamini, shares this binding mode and sequence selectivity (Turner et al, 1999). Alkamin is potently cytotoxic, with an IC 50 value of 7 nM against P388 mouse leukemia cells, has in vivo activity in a stringent single dose assay, and shows a positive hypersensitivity ratio of 15 for activity against a pair of Chinese hamster ovary cell lines designed to reveal whether the mode of drug action involves DNA interstrand cross-links (Prakash et al, 1991;Atwell et al, 1995). In these assays, alkamini is 35-fold less cytotoxic and lacks in vivo activity, pointing to the importance of alkamin cross-links as a major determinant of its biological activity (Atwell et al, 1995).…”

mentioning

confidence: 99%

“…Alkamin is potently cytotoxic, with an IC 50 value of 7 nM against P388 mouse leukemia cells, has in vivo activity in a stringent single dose assay, and shows a positive hypersensitivity ratio of 15 for activity against a pair of Chinese hamster ovary cell lines designed to reveal whether the mode of drug action involves DNA interstrand cross-links (Prakash et al, 1991;Atwell et al, 1995). In these assays, alkamini is 35-fold less cytotoxic and lacks in vivo activity, pointing to the importance of alkamin cross-links as a major determinant of its biological activity (Atwell et al, 1995). As a reference, the clinically used alkylating agent chlorambucil, which reacts virtually exclusively at guanine N7 sites on DNA (Mattes et al, 1986a), has an IC 50 of 6.75 M against P388 leukemia, and the same in vivo efficacy as alkamin but at 25-fold higher doses (Atwell et al, 1995).…”

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confidence: 99%

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Structure of the d(CGCGAATTCGCG)₂Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Majid¹,

Smythe²,

Denny³

et al. 2007

Mol Pharmacol

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Nitrogen mustard alkylating agents are important cancer drugs. Much interest has been focused on redirecting their covalent adducts from the N7 atoms of guanine in the major groove of DNA to the N3 atoms of adenine in the minor groove by attaching mustard groups to AT-selective minor groove binding ligands. Here we describe the use of electrospray ionization and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry to study the structure of the DNA complexes of two minor groove binding polybenzamide mustards, alkamin and alkamini; the former is a bis-half-mustard in which reactive groups are disposed at each end of the ligand, and the latter is its monofunctional analog. Alkamin is potently cytotoxic and active in experimental mouse tumor models, whereas alkamini is not. We have studied their interaction with the DNA dodecamer d(CGCGAATTCGCG) 2 , designated A2T2, and we provide a detailed analysis of the observed DNA-ligand adduct ions and their fragmentation products. We find that alkamini alkylates A2T2 at guanine G4 and adenines A5 and A6 in a manner consistent with covalent attack on purine N3 atoms from the minor groove of the AT tract. Alkamin also forms monofunctional adducts at G4 and both adenines in which the second mustard arm is hydrolyzed but, in addition, forms a variety of interstrand cross-links between adenines A5/A6 and A5Ј/A6Ј, an interstrand cross-link between G4 and A6Ј, and an intrastrand cross-link between G4 and A6. We conclude that the marked cytotoxicity of alkamin and its experimental antitumor activity could be the consequence of its ability to cross-link cellular DNA at AT tract sequences.

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Section: Methodsmentioning

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Structure of the d(CGCGAATTCGCG)₂Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Majid¹,

Smythe²,

Denny³

et al. 2007

Mol Pharmacol

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Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

Denny¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents remain important DNA alkylators. Methotrexate, and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. Cytosine arabinoside and more recent compounds like gemcitabine, fludarabine, cladribine, and pentostatin inhibit DNA polymerase action during DNA synthsis. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs targeted at DNA. The increasing power of organic chemistry increasingly allows the synthesis of close analogs of cytotoxic, but complex, natural products as potential drugs; recent examples are synthetic analogs of the duocarmycins and the epothilones. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy, or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive non‐tumor cell populations.

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SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs

Denny

2010

Burger's Medicinal Chemistry and Drug Discovery

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Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5‐fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents are direct DNA‐modifying agents that still play an important role in clinical treatment. Methotrexate and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs whose therapeutic effects are due to enzyme‐mediated DNA modification. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive nontumor cell populations.

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Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards

Cited by 23 publications

References 23 publications

Structure of the d(CGCGAATTCGCG)₂Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Structure of the d(CGCGAATTCGCG)₂Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs

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Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards

Cited by 23 publications

References 23 publications

Structure of the d(CGCGAATTCGCG)2Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Structure of the d(CGCGAATTCGCG)2Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs

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Structure of the d(CGCGAATTCGCG)₂Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry

Structure of the d(CGCGAATTCGCG)₂Complex of the Minor Groove Binding Alkylating Agent Alkamin Studied by Mass Spectrometry