Novel tertiary sulfonamide derivatives containing benzimidazole moiety as potent anti-gastric cancer agents: Design, synthesis and SAR studies.

With the expectation to find out new anti-gastric cancer agents with high efficacy and selectivity, a series of novel tertiary sulfonamide derivatives were synthesized and the anti-cancer activity was studied in three selected cancer cell lines (MGC-803, PC-3, MCF-7) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells and were more potent than the positive control (5-Fu). The structure-activity relationship of tertiary sulfonamide derivatives was explored in this report. Among the tested compounds, compound 13g containing benzimidazole moiety showed the best anti-proliferation activities against MGC-803 cells (IC50 = 1.02 µM), HGC-27 cells (IC50 = 1.61 µM), SGC-7901 (IC50 = 2.30 µM) cells as well as the good selectivity between the cancer and normal cells. Cellular mechanism studies elucidated compound 13g inhibited the colony formation of gastric cancer cell lines. Meanwhile, compound 13g arrested cell cycle at G2/M phase and induced cell apoptosis. Mechanistically, compound 13g markedly decreased p-Akt and p-c-Raf expression, which revealed that compound 13g targeted gastric cancer cell lines via interfering with AKT/mTOR and RAS/Raf/MEK/ERK pathways. All the findings suggest that compound 13g might be a valuable lead compound for the anti-gastric cancer agents.

Anisotropic shock sensitivity in a single crystal δ-cyclotetramethylene tetranitramine: a reactive molecular dynamics study.

The anisotropic shock sensitivity in a single crystal δ-cyclotetramethylene tetranitramine (δ-HMX) was investigated using the compress-shear reactive dynamics (CS-RD) computational protocol. Significant anisotropies in the thermo-mechanical and chemical responses were found by measuring the shear stress, energy, temperature, and chemical reactions during the dynamical process for the shock directions perpendicular to the (100), (010), (001), (110), (101), (011), and (111) planes. We predict that δ-HMX is sensitive for the shocks perpendicular to the (111), (011), (110), and (101) planes, which is intermediate to the (100) and (010) plane and is insensitive to the (001) plane. The internal energy accumulated within the duration of the surmounting shear stress barrier is a useful criterion to distinguish the sensitive directions from the less sensitive ones. The molecular origin of the anisotropic sensitivity is suggested to be the intermolecular steric arrangements across a slip plane induced by shock compression. The shear deformation induced by the shock along the sensitive direction encounters strong intermolecular contacts and has small intermolecular free space for geometry relaxation when the molecules collide, leading to high shear stress barriers and energy accumulation, which benefits the temperature increase and initial chemical bond breaking that trigger further reactions.