Effect of Molecular Chirality and Side Chain Bulkiness on Angiogenesis of Haloacetylcarbamoyl-2-nitroimidazole Compounds

Abstract

Background: Angiogenesis is required for tumor growth and metastasis, and is an exciting target for cancer treatment. We designed and synthesized antiangiogenetic TX agent (TX-1898, -1900), and analyzed their structural features. TXs have a chiral center and S- and R-enantiomers. Conformation analysis and molecular dynamics simulation were undertaken. Materials and Methods: Molecular models of TXs were constructed using InsightII-Discover. Conformation analysis was performed with CONFLEX, and z-matrix data were extracted to calculate molecular orbital (MO) parameters (i.e. solvation free energy (dGW)). Their molecular dynamics were simulated with the Discover3 module, and the total energy and dihedral angles were estimated. Results: The methyl-including TXs (Group 1: TX-1863, -1878, -1866, -1879) had 130 ~ 229 conformers (-1.26 ~ 14.6 kcal/mol). The t-butyl-including group (Group 2: TX-1880, -1881, -1882, -1883) had 244 ~ 294 conformers (3.69 ~ 16.76 kcal/mol), and the p-t-butylphenyl-containing TXs (Group 3: TX-1897, -1899, -1898, -1900) had 584 ~ 711 conformers (-7.48 ~ 5.18 kcal/mol). The dGW profile of nine samples, which were extracted from these conformers, were examined and one minimum dGW point was observed in the haloacetylcarbamoyl-2-nitroimidazole TXs (Group 1 ~ 3). Conclusion: TX-1898 exhibited significant antiangiogenic activity. The order of antiangiogenic activity was as follows: TX-1898 (93% at 5 μg/pellet) > TX-1900 (82% at 5 μg/pellet) > TX-1897 (64% at 10 μg/pellet) > TX-1899 (58% at 10 μg/pellet). The chiral center has an important role for orienting the molecular characteristics.