Comparative antioxidant, prooxidant and cytotoxic activity of sigmoidin A and eriodictyol

Sigmoidin A (SGN) is a prenylated flavanone derivative of eriodictyol (ERD) with reported moderate antioxidant, antimicrobial and anti-inflammatory activity. Since ERD and other structurally similar antioxidant phenolic compounds have been shown to induce prooxidative macromolecular damage and cytotoxicity in cancer cells, the comparative in vitro effects of these structural analogues on cancer cell viability and Cu(II)-dependent DNA damage were studied. In the presence of Cu(II) ions, both SGN and ERD (7.4-236 µM) caused comparable concentration-dependent pBR322 plasmid DNA strand scission. The DNA damage induced by SGN and ERD could be abolished by ROS scavengers, glutathione (GSH) and catalase as well as EDTA and a specific Cu(I) chelator neocuproine. Both ERD and SGN readily reduce Cu(II) to Cu(I) suggesting a prooxidative mechanism of DNA damage. In a cell free system, ERD and SGN did also show comparable radical scavenging activity. SGN was, however, by an order of magnitude more cytotoxic to cancer cells than ERD and this effect was significantly attenuated by GSH suggesting a prooxidative mechanism of cell death. A depletion of intracellular GSH level by SGN in cancer cells is also demonstrated.

Low temperature X-ray structures of two crystalline forms (I) and (II) of the pyrimidine derivative and sodium channel blocker BW1003C87: 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine

The X-ray crystal structures of two crystalline forms of 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine, C10H7Cl3N4 (code name BW1003C87) (I) and (II), have been carried out at liquid nitrogen temperature. A detailed comparison of the two structures is given. Both are centrosymmetric, with structure (I) in the triclinic space group P (1) over bar unit cell a = 6.4870(10), b = 9.216(2), c = 12.016(2) angstrom, alpha = 75.78(3)degrees, beta = 89.95(3)degrees, gamma = 83.45(3)degrees, V = 691.5(2) angstrom(3), Z = 2 and density (calculated) = 1.544 Mg/m(3); and (II) in the monoclinic space group P2(1)/c, unit cell a = 12.000(2), b = 7.518(2), c = 13.450(3) angstrom, beta = 97.87(3)degrees, V = 1202.0(5) angstrom(3), Z = 4, Density (calculated) = 1.600 Mg/m(3). Structure (I) includes a solvated CH3OH in the lattice. Final R indices [I > 2sigma(I)] are R1 = 0.0427, wR2 = 0.1075 for (I) and R1 = 0.0487, wR2 = 0.1222 for (II). R indices (all data) are R1 = 0.0470, wR2 = 0.1118 for (I) and R1 = 0.0623, wR2 = 0.1299 for (II). 5-Phenyl-2,4 diaminopyrimidine and 6-phenyl-1,2,4 triazine derivatives, which include lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine), have been investigated for some time for their effects on the central nervous system. Both lamotrigine and 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine (code name BW1003C87), the subject of the present study, are anticonvulsant as well as neuroprotective in models of brain ischaemia and in a model of white matter ischaemia. BW1003C87 is a sodium channel blocker which also reduces the release of the neurotransmitter glutamate. The three dimensional structures reported here form part of a newly developed data base for the detailed investigation of members of this drug family and their biological activities.