FLUORINATED ANALOGS OF L-ORNITHINE ARE POWERFUL INHIBITORS OF ORNITHINE DECARBOXYLASE AND CELL-GROWTH OF LEISHMANIA-INFANTUM PROMASTIGOTES

Fluorinated analogues of L-ornithine have been tested on growth and or nithine decarboxylase arising from L.infantum cytosolic extracts. EC(5 0) values estimated from dose/response curves were 38 mu M, 2.62 mu M and 4.64 mu M for alpha-DFMO, Delta-MFMO and Delta-MFMOme respectively . Also the inhibition produced by all three compounds was effectively reverted by exogenous putrescine, pointing towards the inhibition of L .infantum ODC. ODC from logarithmic phase cytosolic extracts was physi cochemically and kinetically characterized, showing a long half-life ( more than 24 h) and a km value for L-ornithine of 98 mu M. Finally, th e inhibitory effect of fluorinated analogues of L-ornithine was analys ed on L.infantum ODC showing a time-dependent irreversible behavior, w ith Ki values estimated on 125 mu M, T-1/2 3.5 min for alpha-DFMO; 13. 3 mu M, T-1/2 1.8 min for Delta-MFMO and 4.3 mu M, T-1/2 4 min for Del ta-MFMOme.