RESUMEN
The compound with R=CH2CH3 in Bi(S2CNR2)3 (1) is highly cytotoxic against a range of human carcinoma, whereas that with R=CH2CH2OH (2) is considerably less so. Both 1 and 2 induce apoptosis in HepG2 cells with some evidence for necrosis induced by 2. Based on DNA fragmentation, caspase activities and human apoptosis PCR-array analysis, both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. While both compounds activate mitochondrial and FAS apoptotic pathways, compound 1 was also found to induce another death receptor-dependent pathway by induction of CD40, CD40L and TNF-R1 (p55). Further, 1 highly expressed DAPK1, a tumour suppressor, with concomitant down-regulation of XIAP and NF-κB. Cell cycle arrest at the S and G2/M phases correlates with the inhibition of the growth of HepG2 cells. The cell invasion rate of 2 is 10-fold higher than that of 1, a finding correlated with the down-regulation of survivin and XIAP expression by 1. Compounds 1 and 2 interact with DNA through different binding motifs with 1 interacting with AT- or TA-specific sites followed by inhibition of restriction enzyme digestion; 2 did not interfere with any of the studied restriction enzymes.
Asunto(s)
Antineoplásicos/farmacología , Bismuto/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , FN-kappa B/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Permeabilidad de la Membrana Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proteínas Quinasas Asociadas a Muerte Celular/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
In the title compound, C(10)H(9)N(3)O(3), there is a small twist between the benzene and triazole rings [dihedral angle = 6.32â (7)°]; the carb-oxy-lic acid residue is almost coplanar with the benzene ring to which it is attached [O-C-C-C torsion angle = 1.49â (19)°]. The main deviation from coplanarity of the non-H atoms is found for the hy-droxy group which is almost perpendicular to the remaining atoms [N-C-C-O torsion angle = -75.46â (16)°]. In the crystal, the presence of O-Hâ¯O (between carboxyl groups) and O-Hâ¯N (between the hy-droxy group and the triazole ring) hydrogen bonds leads to supra-molecular chains along [03[Formula: see text]]. The chains are connected into sheets via C-Hâ¯O(hy-droxy) inter-actions.