Design, synthesis, and in vivo evaluations of benzyl Nω-nitro-Nα-(9H-pyrido[3, 4-b]indole-3-carbonyl)-l-argininate as an apoptosis inducer capable of decreasing the serum concentration of P-selectin12. Issue 9 (9th August 2016) - Xu, Wenyun
Abstract : A series of findings suggest that the discovery of in vivo apoptosis inducers for chemotherapy is of clinical importance. Abstract : A series of findings suggest that the discovery of in vivo apoptosis inducers for chemotherapy is of clinical importance. Based on the analyses of the pharmacophores of in vitro apoptosis inducers, the correlation of P-selectin and apoptosis and the docking investigation benzyl N ω -nitro- N α -(9 H -pyrido[3, 4- b ]indole-3-carbonyl)-l -argininate (NRCB) was designed as a novel nanoscale apoptosis inducer capable of decreasing the serum concentration of P-selectin in vivo . The rationality of the design was confirmed by NRCB effectively promoting the apoptosis of K562 cells in vitro, dose-dependently decreasing the concentration of P-selectin in the serum S180 mice, and the concentration dependently forming nanoparticles. FT-MS and NOESY 2D NMR spectra defined the NRCB forming hexamer as having a triangle like conformation. At 0.01, 0.1, and 1 μmol kg −1 doses, NRCB effectively decreased tumor weights and sizes of S180 mice in a dose-dependent manner, whereby the minimal effective dose was found to be 0.01 μmol kg −1 . At a 1 μmol kg −1 dose, NRCB also effectively inhibited xylene-induced ear edema and decreased the serum TNF-α and IL-2 of the treated mice. The correlations between apoptosis with P-selectin, TNF-α and IL-2 are discussed in particular. In conclusion, NRCB is a novel nano-scale apoptosis inducer capable of decreasing the serum concentration of P-selectin in vivo and could be a promising lead compound of apoptosis inducers for chemotherapy.