Synthesis and cytotoxicity evaluation of some 8-hydroxyquinoline derivatives.

Abstract

Interest in Mannich bases of 8-hydroxyquinoline stems from reports of their high potency against human cancer cells. In the search for potential anticancer drug candidates, Mannich bases of 8-hydroxyquinoline (7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline, 7-piperidinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline) were synthesised by reaction with various secondary amines and formaldehyde. They were prepared as hydrochlorides. The cytotoxic activity of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline compounds in the National Cancer Institute in-vitro cancer cell line panel was determined. It was found that they exhibited substantial cytotoxic activity against leukaemia. The log concentration of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline that inhibited 50% of 60 cell lines' growth were -4.81 M, -5.09 M and -5.35 M, respectively. Compound 7-pyrrolidinomethyl-8-hydroxyquinoline was selected for further in-vivo testing. The electrophysiological effect of 7-pyrrolidinomethyl-8-hydroxyquinoline also was tested in human myeloma cells (RPMI 8226). The outward current was voltage dependent, activating at -40 mV and believed to be the voltage-activated K+ current I(K(V)). 7-Pyrrolidinomethyl-8-hydroxyquinoline (1-30 microM) caused the inhibition of I(K(V)) in a concentration-dependent manner. The IC50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of I(K(V)) is 23 microM. The GI50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of cell growth is 14 microM. The results suggest that at least part of the cytotoxicity effect of 7-pyrrolidinomethyl-8-hydroxyquinoline on myeloma cells could be related to blockade of voltage-activated K+ channels.

• Authors: A Y Shen, S N Wu, C T Chiu
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 51 Issue 5 Pg. 543-8 (May 1999) ISSN: 0022-3573 [Print] England
• PMID: 10411213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-morpholinomethyl-8-hydroxyquinoline
• Antineoplastic Agents
• Hydroxyquinolines
• Morpholines
• Potassium Channels
• Oxyquinoline

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Hydroxyquinolines (chemical synthesis, pharmacology)
• Morpholines (chemical synthesis, pharmacology)
• Oxyquinoline (analogs & derivatives, chemical synthesis, pharmacology)
• Potassium Channels (drug effects)
• Tumor Cells, Cultured