Bromophenol is a type of natural marine product. It has excellent biological activities, especially anticancer activities. In our study of searching for potent anticancer drugs, a novel bromophenol derivative containing indolin-2-one moiety, 3-(4-(3-([1,4′-bipiperidin]-1′-yl)propoxy)-3-bromo-5-methoxybenzylidene)-N-(4-bromophenyl)-2-oxoindoline-5-sulfonamide (BOS-102) was synthesized, which showed excellent anticancer activities on human lung cancer cell lines. A study of the mechanisms indicated that BOS-102 could significantly block cell proliferation in human A549 lung cancer cells and effectively induce G0/G1 cell cycle arrest via targeting cyclin D1 and cyclin-dependent kinase 4 (CDK4). BOS-102 could also induce apoptosis, including activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP, ΔΨ_m), and leading cytochrome c release from mitochondria. Further research revealed that BOS-102 deactivated the PI3K/Akt pathway and activated the mitogen-activated protein kinase (MAPK) signaling pathway resulting in apoptosis and cell cycle arrest, which indicated that BOS-102 has the potential to develop into an anticancer drug.

Bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol compound derived from marine algae. Previous reports have shown that BDDPM possesses antimicrobial activity. In the present study, we found that BDDPM has cytotoxic activity on a wide range of tumor cells, including BEL-7402 cells (IC₅₀ = 8.7 μg/mL). Further studies have shown that prior to the onset of apoptosis, the BDDPM induces BEL-7402 cell detachment by decreasing the adherence of cells to the extracellular matrix (ECM). Detachment experiments have shown that the treatment of BEL-7402 cells with low concentrations of BDDPM (5.0 μg/mL) significantly inhibits cell adhesion to fibronectin and collagen IV as well as cell migration and invasion. High doses of BDDPM (10.0 μg/mL) completely inhibit the migration of BEL-7402 cells, and the expression level of MMPs (MMP-2 and MMP-9) is significantly decreased. Moreover, the expression of β1-integrin and focal adhesion kinase (FAK) is found to be down-regulated by BDDPM. This study suggests that BDDPM has a potential to be developed as a novel anticancer therapeutic agent due to its anti-metastatic activity and also indicates that BDDPM, which has a unique chemical structure, could serve as a lead compound for rational drug design and for future development of anticancer agents.

Endothelial dysfunction is a critical factor during the initiation of atherosclerosis. Berberine has a beneficial effect on endothelial function; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of berberine on lipopolysaccharide‐ (LPS‐) induced apoptosis in human umbilical vein endothelial cells (HUVECs) and the molecular mechanisms mediating the effect. The effects of berberine on LPS‐induced cell apoptosis and viability were measured with 5‐ethynyl‐2′‐deoxyuridine staining, flow cytometry, and Cell Counting Kit‐8 assays. The expression and/or activation of proapoptotic and antiapoptotic proteins or signaling pathways, including caspase‐3, poly(ADP‐ribose) polymerase, myeloid cell leukemia‐1 (MCL‐1), p38 mitogen‐activated protein kinase, C‐Jun N‐terminal kinase (JNK), and extracellular signal‐regulated kinase, were determined with western blotting. The malondialdehyde levels, superoxide dismutase (SOD) activity, and production of proinflammatory cytokines were measured with enzyme‐linked immunosorbent assays. The results demonstrated that berberine pretreatment protected HUVECs from LPS‐induced apoptosis, attenuated LPS‐induced injury, inhibited LPS‐induced JNK phosphorylation, increased MCL‐1 expression and SOD activity, and decreased proinflammatory cytokine production. The effects of berberine on LPS‐treated HUVECs were prevented by SP600125, a JNK‐specific inhibitor. Thus, berberine might be a potential candidate in the treatment of endothelial cell injury‐related vascular diseases.

Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a bromophenol first isolated from Rhodomelaceae confervoides. Our previous studies showed that BDDPM exerts PTP1B-inhibiting activity and anti-cancer activity against a wide range of tumor cells while it also showed lower cytotoxicity against normal cells. In the present study, we found that BDDPM exhibits significant activities toward angiogenesis in vitro. BDDPM inhibits multiple angiogenesis processes, including endothelial cell sprouting, migration, proliferation, and tube formation. Further kinase assays investigations found that BDDPM is a potent selective, but multi-target, receptor tyrosine kinase (RTKs) inhibitor. BDDPM (10 μM) inhibits the activities of fibroblast growth factor receptor 2 and 3 (FGFR2, 3), vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor α (PDGFRα) (inhibition rate: 57.7%, 78.6%, 78.5% and 71.1%, respectively). Moreover, BDDPM also decreases the phosphorylation of protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS), as well as nitric oxide (NO) production in a dose dependent manner. These results indicate that BDDPM can be exploited as an anti-angiogenic drug, or as a lead compound for the development of novel multi-target RTKs inhibitors.