Discovery of potent 4-aminoquinoline hydrazone inhibitors of NRH:quinoneoxidoreductase-2 (NQO2).

Abstract

(NRH):quinone oxidoreductase 2 (NQO2) is associated with various processes involved in cancer initiation and progression probably via the production of ROS during quinone metabolism. Thus, there is a need to develop inhibitors of NQO2 that are active in vitro and in vivo. As part of a strategy to achieve this we have used the 4-aminoquinoline backbone as a starting point and synthesized 21 novel analogues. The syntheses utilised p-anisidine with Meldrum's acid and trimethyl orthoacetate or trimethyl orthobenzoate to give the 4-hydrazin-quinoline scaffold, which was derivatised with aldehydes or acid chlorides to give hydrazone or hydrazide analogues, respectively. The hydrazones were the most potent inhibitors of NQO2 in cell free systems, some with low nano-molar IC50 values. Structure-activity analysis highlighted the importance of a small substituent at the 2-position of the 4-aminoquinoline ring, to reduce steric hindrance and improve engagement of the scaffold within the NQO2 active site. Cytotoxicity and NQO2-inhibitory activity in vitro was evaluated using ovarian cancer SKOV-3 and TOV-112 cells (expressing high and low levels of NQO2, respectively). Generally, the hydrazones were more toxic than hydrazide analogues and further, toxicity is unrelated to cellular NQO2 activity. Pharmacological inhibition of NQO2 in cells was measured using the toxicity of CB1954 as a surrogate end-point. Both the hydrazone and hydrazide derivatives are functionally active as inhibitors of NQO2 in the cells, but at different inhibitory potency levels. In particular, 4-((2-(6-methoxy-2-methylquinolin-4-yl)hydrazono)methyl)phenol has the greatest potency of any compound yet evaluated (53 nM), which is 50-fold lower than its toxicity IC50. This compound and some of its analogues could serve as useful pharmacological probes to determine the functional role of NQO2 in cancer development and response to therapy.

• Authors: Buthaina Hussein, Balqis Ikhmais, Manikandan Kadirvel, Rachael N Magwaza, Gavin Halbert, Richard A Bryce, Ian J Stratford, Sally Freeman
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 182 Pg. 111649 (Nov 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31514018 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Aminoquinolines
• Enzyme Inhibitors
• Hydrazones
• NRH - quinone oxidoreductase2
• Quinone Reductases
• 4-aminoquinoline

Topics

• Aminoquinolines (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Hydrazones (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Quinone Reductases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Tumor Cells, Cultured