Vieites Marisol, Noblía Pabla, Torre María H, Cerecetto Hugo, Laura Lavaggi María, Costa-Filho Antonio J, Azqueta Amaia, de Cerain Adela López, Monge Antonio, Parajón-Costa Beatriz, González Mercedes, Gambino Dinorah
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800 Montevideo, Uruguay.
J Inorg Biochem. 2006 Aug;100(8):1358-67. doi: 10.1016/j.jinorgbio.2006.03.012. Epub 2006 Apr 25.
A new vanadyl complex with the formula VO(L1)2, where L1=3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1), N(4)-dioxide, has been synthesized and characterized by elemental analyses, conductometry, fast atom bombardment mass spectroscopy (FAB-MS) and electronic, Fourier transform infrared (FTIR), Raman, nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopies. Results were compared with those previously reported for analogous vanadium complexes with other 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands. As an effort to develop novel metal-based selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of aminoquinoxaline carbonitrile N-dioxides bioreductive prodrugs, the new complex and VO(L)2 complexes, with L=3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide (L2) and 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide (L3), were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes resulted in vitro more potent cytotoxins than the free ligands (i.e. potencies P(VO(L1)2)=3.0, P(L1)=9.0 microM) and Tirapazamine (P=30.0 microM) and showed excellent selective cytotoxicity in hypoxia, being no cytotoxic in oxia. In addition, the solubility in hydrophilic solvents resulted significantly higher for the vanadyl complexes than for the free ligands. These results could be indicative that complexation of the quinoxaline-2-carbonitrile N1,N4-dioxide derivatives with vanadium could improve their bioavailability. In addition, a new aspect of the series has been investigated. A detailed comparison of the electrochemical behavior of the free ligands and the complexes has been performed searching for a correlation between reduction potentials of the complexes and their activities and hypoxia selectivities.
一种新的钒基配合物，化学式为VO(L1)2，其中L1 = 3-氨基-6(7)-氯喹喔啉-2-甲腈N(1), N(4)-二氧化物，已通过元素分析、电导法、快原子轰击质谱(FAB-MS)以及电子、傅里叶变换红外(FTIR)、拉曼、核磁共振(NMR)和电子顺磁共振(EPR)光谱进行了合成与表征。将结果与先前报道的以其他3-氨基喹喔啉-2-甲腈N1,N4-二氧化物衍生物作为配体的类似钒配合物的结果进行了比较。为了开发新型金属基选择性缺氧细胞毒素，并提高氨基喹喔啉甲腈N-二氧化物生物还原前药的生物利用度以及药理和毒理学性质，对新配合物以及VO(L)2配合物[其中L = 3-氨基-6(7)-溴喹喔啉-2-甲腈N1,N4-二氧化物(L2)和3-氨基-6(7)-甲基喹喔啉-2-甲腈N1,N4-二氧化物(L3)]在缺氧和好氧条件下的V79细胞中进行了细胞毒性评估。这些配合物在体外比游离配体具有更强的细胞毒性(即效力P(VO(L1)2)=3.0，P(L1)=9.0 microM)以及替拉帕米(P = 30.0 microM)，并且在缺氧条件下表现出优异的选择性细胞毒性，在有氧条件下无细胞毒性。此外，钒基配合物在亲水性溶剂中的溶解度明显高于游离配体。这些结果可能表明喹喔啉-2-甲腈N1,N4-二氧化物衍生物与钒的络合可以提高它们的生物利用度。此外，还对该系列的一个新方面进行了研究。对游离配体和配合物的电化学行为进行了详细比较，以寻找配合物的还原电位与其活性和缺氧选择性之间的相关性。
