Cytotoxic palladium complexes of bioreductive quinoxaline N1,N4-dioxide prodrugs |
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| Authors: | Carolina Urquiola Marisol Vieites María H Torre Mauricio Cabrera María Laura Lavaggi Hugo Cerecetto Mercedes González Adela López de Cerain Antonio Monge Pablo Smircich Beatriz Garat Dinorah Gambino |
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| Institution: | 1. Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800 Montevideo, Uruguay;2. Departamento de Química Orgánica, Facultad de Química – Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay;3. Unidad en I+D de Medicamentos, CIFA, Universidad de Navarra, Irunlarrea s/n, 31080 Pamplona, Spain;4. Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay |
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| Abstract: | Four new palladium(II) complexes with the formula Pd(L)2, where L are quinoxaline-2-carbonitrile N1,N4-dioxide derivatives, were synthesized as a contribution to the chemistry and pharmacology of metal compounds with this class of pharmacologically interesting bioreductive prodrugs. Compounds were characterized by elemental, conductometric and thermogravimetric analyses, fast atom bombardment mass spectrometry (FAB-MS) and electronic, Fourier transform infrared (FTIR) and 1H-nuclear magnetic resonance spectroscopies. The complexes were subjected to cytotoxic evaluation on V79 cells in hypoxic and aerobic conditions. In addition, a preliminary study on interaction with plasmid DNA in normoxia was performed. Complexes showed different in vitro biological behavior depending on the nature of the substituent on the quinoxaline ring. Pd(L1)2 and Pd(L2)2, where L1 is 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide and L2 is 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide, showed non selective cytotoxicity, being cytotoxic either in hypoxic or in aerobic conditions. On the other hand, Pd(L3)2, where L3 is 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N1,N4-dioxide, resulted in vitro more potent cytotoxin in hypoxia (P = 5.0 μM) than the corresponding free ligand (P = 9.0 μM) and tirapazamine (P = 30.0 μM), the first bioreductive cytotoxic drug introduced into clinical trials. In addition, it showed a very good selective cytotoxicity in hypoxic conditions, being non-cytotoxic in normoxia. Its hypoxic cytotoxicity relationship value, HCR, was of the same order than those of other hypoxia selective cytotoxins (i.e., Mitomycine C, Misonidazole and the N-oxide RB90740). Interaction of the complexes with plasmid DNA in normoxia showed dose dependent ability to relax the negative supercoiled forms via different mechanisms. Pd(L2)2 introduced a scission event in supercoiled DNA yielding the circular relaxed form. Meanwhile, both Pd(L1)2 and Pd(L3)2 produced the loss of negative supercoils rendering a family of topoisomers with reduced electrophoretic mobility. Pd(L3)2 showed a more marked effect than Pd(L1)2. Indeed, for the highest doses assayed, Pd(L3)2 was even able to introduce positive supercoils on the plasmid DNA. |
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