Discovery of novel 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives as potent carbonic anhydrase IX inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer.

A novel series of 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives were designed and synthesized as carbonic anhydrase IX (CA IX) inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer (TNBC). The representative compound 9o exhibited more potent inhibitory activity and selective against CA IX over off-target CA II, compared with positive control SLC-0111. Molecular docking study was also performed to gain insights into the binding interactions of 9o in the binding pocket of CAIX. Moreover, compound 9o exhibited superior antitumor activities against breast cancer cells under hypoxia than that of normoxia conditions. Mechanism studies revealed that compound 9o could act as DNA intercalator and effectively suppressed cell migration, arrested the cell cycle at G1/S phase and induced apoptosis in MDA-MB-231 cells, while inducing ferroptosis accompanied by the dissipation of MMP and the elevation intracellular levels of ROS. Notably, in vivo studies demonstrated that 9o effectively inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4 T1 xenograft model. Taken together, this study suggests that compound 9o represents a potent and selective CA IX inhibitor and ferroptosis inducer for the treatment of TNBC.

Climate and soil stressed elevation patterns of plant species to determine the aboveground biomass distributions in a valley-type Savanna.

Introduction: Extreme environments such as prolonged high temperatures and droughts can cause vulnerability of vegetation ecosystems. The dry-hot valleys of Southwestern China, known for their extremely high annual temperature, lack of water, and unique non-zonal "hot island" habitat in the global temperate zone, provide exceptional sites for studying how plant adapts to the prolonged dry and hot environment. However, the specific local biotic-environment relationships in these regions remain incompletely elucidated. The study aims to evaluate how valley-type Savanna vegetation species and their communities adapt to long-term drought and high-temperature stress environments. Methods: The study investigated the changes in species diversity and communities' aboveground biomass of a valley-type Savanna vegetation along an elevation gradient of Yuanmou dry-hot valley in Jinsha River basin, southwest China. Subsequently, a general linear model was utilized to simulate the distribution pattern of species diversities and their constituent biomass along the elevation gradient. Finally, the RDA and VPH mothed were used to evaluate the impacts and contributions of environmental factors or variables on the patterns. Results and discussion: The field survey reveals an altitudinal gradient effect on the valley-type Savanna, with a dominant species of shrubs and herbs plants distribution below an elevation of 1700m, and a significant positive relationship between the SR, Shannon-Wiener, Simpson, and Pielou indices and altitudes. Relatively, the community aboveground biomass did not increase significantly with elevation, which was mainly due to a decreased biomass of herbaceous plants along the elevation. Different regulators of shrub-herbaceous plant species and their functional groups made different elevation patterns of species diversity and aboveground biomass in valley-type Savannas. Herbaceous plants are responsible for maintaining species diversity and ensuring stability in the aboveground biomass of the vegetation. However, the influence of shrubs on aboveground biomass became more pronounced as environmental conditions varied along the altitudinal gradient. Furthermore, species diversity was mainly influenced by soil and climatic environmental factors, whereas community biomass was mainly regulated by plant species or functional groups. The study demonstrates that the spatial pattern of valley-type Savanna was formed as a result of different environmental responses and the productive capacity of retained plant species or functional groups to climate-soil factors, highlighting the value of the Yuanmou dry-hot Valley as a microcosm for exploring the intricate interactions between vegetation evolution and changes in environmental factors.