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Liang, Liyun, Wang, Haiwen, Du, Yongliang, Luo, Bingling, Meng, Ning, Cen, Meifeng, Huang, Peng, Ganesan, A. 
ORCID: https://orcid.org/0000-0003-4862-7999 and Wen, Shijun
(2020)
New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: design, synthesis and biological evaluation.
Bioorganic Chemistry, 99.
ISSN 0045-2068
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Abstract
Lysine-specific demethylase 1 (LSD1) is frequently elevated in acute myeloid leukemia (AML) and often leads to tumorigenesis. In recent years, numerous LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have reached clinical trials. Most TCP derivatives were modified at the amino site of cyclopropane motif. Herein, we for the first time introduced a sulfonamide group in TCP benzene ring of series a compounds and performed a systematical study on structure and activity relationships by varying sulfonamide groups. The introduction of sulfonamide significantly increased the targeting capacity of TCP against LSD1. Moreover, we discovered that the Boc attached LSD1 inhibitors (labelled as series b compounds) substantially improved their anti-proliferation capacity towards AML cells. The intracellular thermal shift and LC-MS/MS results implied that Boc enhanced the drug lipophilicity and might be removed under the cancerous acidic environment to release the real pharmacophore, evidenced by the fact that a structurally similar but acidic inert pivaloyl to replace Boc dramatically dropped the cellular anti-proliferation effect. Finally, a benzyl group installed at the amino site to appropriately increase lipophilicity led to trans-4-(2-(benzylamino)-cyclopropyl)-N,N-diethylbenzenesulfonamide a10 that showed better anti-proliferation activity in AML cells and enzymatic inhibition against LSD1. Taken together, our work offers a novel TCP-based structure and provides a prodrug strategy for the discovery of potent LSD1 inhibitors by having appropriate lipophilicity.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | acute myeloid leukemia,inhibitor,lipophilicity,lysine-specific demethylase 1,prodrug,biochemistry,molecular biology,drug discovery,organic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
| Faculty \ School: | Faculty of Science > School of Pharmacy |
| UEA Research Groups: | Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 22 Apr 2020 08:49 |
| Last Modified: | 22 Oct 2022 06:03 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/74821 |
| DOI: | 10.1016/j.bioorg.2020.103808 |
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