Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase.
Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase.
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DOI：
10.1016/j.bmcl.2012.08.008
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发表时间：
2012-10-01
影响因子：
2.7
通讯作者：
Sartorelli, Alan C.
中科院分区：
文献类型：
--
作者：
Zhu, Rui;Seow, Helen A.;Baumann, Raymond P.;Ishiguro, Kimiko;Penketh, Philip G.;Shyam, Krishnamurthy;Sartorelli, Alan C.
The efficacy of agents that alkylate the O-6 position of guanine is inhibited by O6-alkylguanine-DNA alkyltransferase (AGT) which removes these lesions from the tumor DNA. To increase differential toxicity, inhibitors must selectively deplete AGT in tumors, while sparing normal tissues where this protein serves a protective function. A newly synthesized prodrug of the AGT inhibitor O6-benzylguanine (O6-BG) with an α,α-dimethyl-4-nitrobenzyloxycarbonyl moiety masking the essential 2-amino group has demonstrated the feasibility of targeting hypoxic regions that are unique to solid tumors, for drug delivery. However, these modifications resulted in greatly decreased solubility. Recently, new potent global AGT inhibitors with improved formulatability such as O6-[(3-aminomethyl)benzylguanine (1) have been developed. However, acetylamino (N-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)acetamide) (2) exhibits a pronounced decrease in activity. Thus, 1 would be inactivated by N-acetylation and probably N-glucuronidation. To combat potential conjugational inactivation while retaining favorable solubility, we synthesized 6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-amine (3) in which the 3-aminomethyl moiety is protected by methylation; and to impart tumor selectivity we synthesized 2-(4-nitrophenyl)propan-2-yl(6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-yl)carbamate (7), a hypoxia targeted prodrug of 3 utilizing an α,α-dimethyl-4-nitrobenzyloxycarbonyl moiety. Consistent with this design, 7 demonstrates both hypoxia selective conversion by EMT6 cells of 7 to 3 and hypoxic sensitization of AGT containing DU145 cells to the cytotoxic actions of laromustine, while exhibiting improved solubility.
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影响因子：
3.4
作者：
Baumann RP;Penketh PG;Seow HA;Shyam K;Sartorelli AC
通讯作者：
Sartorelli AC
影响因子：
3.1
作者：
Baumann, RP;Seow, HA;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
5.9
作者：
CALDWELL, J
通讯作者：
CALDWELL, J
影响因子：
7.3
作者：
Pauly GT;Loktionova NA;Fang Q;Vankayala SL;Guida WC;Pegg AE
通讯作者：
Pegg AE
影响因子：
2.9
作者：
Ishiguro, Kimiko;Shyam, Krishnamurthy;Sartorelli, Alan C.
通讯作者：
Sartorelli, Alan C.