Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6‑Methylguanine-DNA-methyltransferase, DNA Mismatch Repair, and p53
The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53...
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| Published in | Journal of medicinal chemistry Vol. 56; no. 17; pp. 7120 - 7132 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
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WASHINGTON
American Chemical Society
12.09.2013
Amer Chemical Soc |
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| Abstract | The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure–activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed. |
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| AbstractList | The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed. The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O 6-methylguanine ( O 6-MeG), by O 6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine- N 7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p -tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine- N 7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed. The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed.The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed. |
| Author | Li, Li Wheelhouse, Richard T Phillips, Roger M Pletsas, Dimitrios Garelnabi, Elrashied A. E |
| AuthorAffiliation | School of Pharmacy Institute of Cancer Therapeutics University of Bradford |
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| Author_xml | – sequence: 1 givenname: Dimitrios surname: Pletsas fullname: Pletsas, Dimitrios – sequence: 2 givenname: Elrashied A. E surname: Garelnabi fullname: Garelnabi, Elrashied A. E – sequence: 3 givenname: Li surname: Li fullname: Li, Li – sequence: 4 givenname: Roger M surname: Phillips fullname: Phillips, Roger M – sequence: 5 givenname: Richard T surname: Wheelhouse fullname: Wheelhouse, Richard T email: r.t.wheelhouse@brad.ac.uk |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23895620$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1158/1541-7786.MCR-12-0168 10.1073/pnas.2331323100 10.1021/ml300132t 10.1038/nrc2292 10.1016/j.ejmech.2005.11.007 10.1159/000327837 10.1021/jo9012699 10.1158/0008-5472.CAN-08-1687 10.1016/j.ygyno.2004.03.020 10.1158/1078-0432.CCR-07-1719 10.1128/MCB.23.22.8306-8315.2003 10.1093/bmb/ldl020 |
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| Keywords | THERAPY-RELATED CANCER ANTITUMOR DRUG TEMOZOLOMIDE IN-VITRO METHYLATING AGENTS METHYLTRANSFERASE MECHANISM DISCOVERY SCREEN DECOMPOSITION ALKYLTRANSFERASE MITOZOLOMIDE |
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| Snippet | The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion,... The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion,... |
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| SubjectTerms | Base Pair Mismatch Chemistry, Medicinal DNA Repair Life Sciences & Biomedicine O-Methylguanine-DNA Methyltransferase - chemistry Pharmacology & Pharmacy Prodrugs - chemistry Quantitative Structure-Activity Relationship Science & Technology Tumor Suppressor Protein p53 - metabolism |
| Title | Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6‑Methylguanine-DNA-methyltransferase, DNA Mismatch Repair, and p53 |
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