title: Comparative study of the effects of 1,3,4-thiadiazolium mesoionic derivatives on energy-linked functions of rat liver mitochondria.
abstract: The main goal of this work was to investigate the relationship between the effects of three new 1,3,4-thiadiazolium mesoionic derivatives on mitochondrial bioenergetics and their previously described chemical structure and antimelanoma activity. The 4-phenyl-5-(2'-Y, 4'-X or 4'-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chlorides differed from each other only in the cinnamoyl ring substituent: MI-J, X=OH; MI-F, X=F; MI-2,4diF X=Y=F. The state 3 respiratory rate was strongly decreased by all derivatives, reaching total inhibition of MI-4F and MI-2,4diF (130nmolmg(-1) protein), when glutamate plus malate were used as substrate. State 3 inhibition was less accentuated with succinate as substrate. Analyses of segments of the respiratory chain indicated complexes I and IV as sites inhibited by the derivatives. State 4 respiration was strongly stimulated by the three derivatives, and was characterized as an uncoupling effect, which was more intense for MI-4F. This stimulus was so pronounced that the values of RCC and ADP/O ratio were only calculated for the lowest concentration (6.5nmolmg(-1) protein). In intact mitochondria, the ATPase activity was increased dramatically by approximately 120%, approximately 207% and approximately 261% for MI-J, MI-4F and MI-2,4diF (32.5nmolmg(-1) protein), respectively. In conclusion, the presence of fluorine substituent in the cinnamoyl ring intensifies the effect of mesoionic compounds on mitochondrial functions and, in this context, hydrophobicity is more important than the electronic effect, which was correlated to antimelanoma activity described previously for these compounds.
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Amanda do Rocio Andrade
authors.initials: Ado R
authors.lastname: Pires
authors.forename: Maria Benigna Martinelli
authors.initials: MB
authors.lastname: de Oliveira
authors.forename: Aurea
authors.initials: A
authors.lastname: Echevarria
authors.forename: Edson Fernandes
authors.initials: EF
authors.lastname: Silva
authors.forename: Maria Eliane Merlin
authors.initials: ME
authors.lastname: Rocha
authors.forename: Eva Gunilla Skare
authors.initials: EG
authors.lastname: Carnieri
authors.forename: Glaucia Regina
authors.initials: GR
authors.lastname: Martinez
authors.forename: Guilhermina Rodrigues
authors.initials: GR
authors.lastname: Noleto
authors.forename: Silvia Maria Suter Correia
authors.initials: SM
authors.lastname: Cadena
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D056152:Respiratory Rate / Q000187:drug effects; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D013830:Thiadiazoles; D000251:Adenosine Triphosphatases