1. From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action.
- Author
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Tran QTN, Tan DWS, Wong WSF, and Chai CLL
- Subjects
- Acute Lung Injury drug therapy, Animals, Anti-Inflammatory Agents therapeutic use, Diterpenes therapeutic use, Mice, Sulfhydryl Compounds chemistry, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacology, Diterpenes chemistry, Diterpenes pharmacology, Drug Design
- Abstract
Covalent drugs with prolonged actions often show superior potency, yet integrated strategies for optimizing their structural and electronic features are lacking. Herein, we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical and biological conditions. The cell-based SAR studies permitted the assessment of the inhibitor efficacy in more complex systems, which were often limited in traditional covalent drug development using isolated proteins or peptides. Our in vitro study identified enone 17 as the most promising candidate which demonstrated potent anti-inflammatory activity and superior safety profiles as compared to the lead compound andrographolide. Its reversibility following a Michael addition reaction with biological thiols resulted in more predictable pharmacological responses. In addition, 17 exhibited good in vivo efficacy at doses as low as 0.3 mg/kg when tested in LPS-induced acute lung injury model. Given a good balance of chemical reactivity and biological potency, enone 17 potentially offers a new therapeutic option based on natural product chemistry for the management of inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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