1055972-09-2Relevant academic research and scientific papers
Inhibitor of low-oxygen targeted tumor cell DNA repair enzyme methylguanine methyl transferase (MGMT), and preparation method and application of inhibitor
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Paragraph 0061; 0070; 0073; 0074, (2019/05/16)
The invention discloses an inhibitor of low-oxygen targeted tumor cell DNA repair enzyme methylguanine methyl transferase (MGMT), and a preparation method and application of the inhibitor. The structural formula of the compound disclosed by the invention
Synthesis and antitumor activity evaluation of a novel combi-nitrosourea prodrug: Designed to release a DNA cross-linking agent and an inhibitor of O6-alkylguanine-DNA alkyltransferase
Sun, Guohui,Zhang, Na,Zhao, Lijiao,Fan, Tengjiao,Zhang, Shufen,Zhong, Rugang
, p. 2097 - 2107 (2016/04/20)
The drug resistance of CENUs induced by O6-alkylguanine-DNA alkyltransferase (AGT), which repairs the O6-alkylated guanine and subsequently inhibits the formation of dG-dC cross-links, hinders the application of CENU chemotherapies. Therefore, the discovery of CENU analogs with AGT inhibiting activity is a promising approach leading to novel CENU chemotherapies with high therapeutic index. In this study, a new combi-nitrosourea prodrug 3-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)-1-(2-chloroethyl)-1-nitrosourea (6), designed to release a DNA cross-linking agent and an inhibitor of AGT, was synthesized and evaluated for its antitumor activity and ability to induce DNA interstrand cross-links (ICLs). The results indicated that 6 exhibited higher cytotoxicity against mer+ glioma cells compared with ACNU, BCNU, and their respective combinations with O6-benzylguanine (O6-BG). Quantifications of dG-dC cross-links induced by 6 were performed using HPLC-ESI-MS/MS. Higher levels of dG-dC cross-link were observed in 6-treated human glioma SF763 cells (mer+), whereas lower levels of dG-dC cross-link were observed in 6-treated calf thymus DNA, when compared with the groups treated with BCNU and ACNU. The results suggested that the superiority of 6 might result from the AGT inhibitory moiety, which specifically functions in cells with AGT activity. Molecular docking studies indicated that five hydrogen bonds were formed between the O6-BG analogs released from 6 and the five residues in the active pocket of AGT, which provided a reasonable explanation for the higher AGT-inhibitory activity of 6 than O6-BG.
A β-chloro ethylnitrosourea compound and its synthetic method and use
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, (2017/01/17)
The invention relates to novel beta-chloroethylnitrosourea compounds, and a synthesis method and application thereof. The structure of the beta-chloroethylnitrosourea compounds is disclosed as general formula (II). The in-vitro antitumor screening test on the compounds disclosed as general formula II proves that the compounds disclosed as general formula I have obvious inhibiting action on human cerebral nerve glioma cells SF763, SF767, SF126 and SF188, human colon cancer cell HT29, mouse leukaemia cell L1210 and many other tumor cell lines and have higher tumor inhibiting activity than the existing CENU and CENU/O6-benzylguanine combined medicine.
Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6- benzylguanine
Pauly, Gary T.,Loktionova, Natalia A.,Fang, Qingming,Vankayala, Sai Lakshmana,Guida, Wayne C.,Pegg, Anthony E.
experimental part, p. 7144 - 7153 (2009/11/30)
O6-Benzylguanine is an irreversible inactivator of O 6-alkylguanine-DNA alkyltransferase currently in clinical trials to overcome alkyltransferase-mediated resistance to certain cancer chemotherapeutic alkylating agents. In order to produce more soluble alkyltransferase inhibitors, we have synthesized three aminomethyl-substituted O 6-benzylguanines and the three methyl analogs and found that the substitution of aminomethyl at the meta-position greatly enhances inactivation of alkyltransferase, whereas para-substitution has little effect and ortho-substitution virtually eliminates activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R2) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED50) values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein.
