Synthesis and cytotoxicity properties of amiodarone analogues.
Amiodarone (AMI) is a potent antiarrhythmic agent; however, its clinical use is limited due to numerous side effects. In order to investigate the structure--cytotoxicity relationship, AMI analogues were synthesized, and then, using rabbit alveolar macrophages, were tested for viability and for the ability to interfere with the degradation of surfactant protein A (SP-A) and with the accumulation of an acidotropic dye. Our data revealed that modification of the diethylamino-beta-ethoxy group of the AMI molecule may affect viability, the ability to degrade SP-A and vacuolation differently. In particular, PIPAM (2d), an analogue with a piperidyl moiety, acts toward the cells in a similar manner to AMI, but is less toxic. Thus, it would be possible to reduce the cytotoxicity of AMI by modifying its chemical structure.
Bigler
Laurent
L
Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Spirli
Carlo
C
Fiorotto
Romina
R
Pettenazzo
Andrea
A
Duner
Elena
E
Baritussio
Aldo
A
Follath
Ferenc
F
Ha
Huy Riem
HR
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects; D015394:Molecular Structure; D011663:Pulmonary Surfactants; D011817:Rabbits
D000970:Antineoplastic Agents; D011663:Pulmonary Surfactants; D000638:Amiodarone