P-glycoprotein (P-gp) inhibition has been studied to overcome multidrug resistance in cancer chemotherapy but failed in clinical trials due to low/toxic effects. Recently, a dual modulation of transporters and natural derivatives have been examined to surmount this limitation. We examined breast cancer resistance protein (BCRP) inhibition in vitro and in vivo by P-gp inhibitors derived from natural compounds in previous studies. P-gp inhibitors increased the accumulation of the anticancer drug, topotecan (TPT)—a substrate of P-gp and BCRP, albeit with higher affinity for BCRP—in BCRP-overexpressing cells, resulting in cell death. These dual inhibitors, when orally co-administered with TPT, enhanced TPT bioavailability with slightly reduced total oral clearance (Clt/F) in rats. In xenograft mice, they strengthened oral TPT-induced tumor reduction with no alterations in body weight. Moreover, we investigated the effects of an oral drug formulation (Cremophor® EL, Tween® 80, and polyethylene glycol 400) on the transporters function. The excipients increased TPT accumulation in P-gp- or BCRP-overexpressing cells. Oral TPT bioavailability was higher with the formulation than with a control, as shown by the increases in the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve from zero to infinity (AUCINF) (p < 0.01). Therefore, oral TPT bioavailability was enhanced by P-gp/BCRP dual inhibition, which resulted in a formulation-mediated increase in absorption and decrease in elimination, and a dual inhibitor-mediated decrease in elimination. These results suggest that the combination of dual inhibition by a natural derivative and the drug formulation can be a useful clinical approach.
AIMP2-DX2, a splicing variant of AIMP2, is upregulated in lung cancer, possesses oncogenic activity, and results in tumorigenesis. Specifically inhibiting the interaction between AIMP2-DX2 and HSP70 to suppress AIMP2-DX2-dependent cancers with small molecules is considered a promising avenue for cancer therapeutics. Optimization of hit BC-DXI-04 (IC 50 = 40.1 μM) provided new potent sulfonamide based AIMP2-DX2 inhibitors. Among these, BC-DXI-843 showed improved inhibition against AIMP2-DX2 (IC 50 = 0.92 μM) with more than 100fold selectivity over AIMP2 in a luciferase assay. Several binding assays indicated that this compound effectively induces cancer cell apoptosis by specifically interrupting the interaction between DX2 and HSP70, which leads to the degradation of DX2 via Siah1mediated ubiquitination. More importantly, BC-DXI-843 demonstrated in vivo efficacy in a tumor xenograft mouse model (H460 cells) at a dosage of 50 mg/kg, suggesting it as a promising lead for development of novel therapeutics targeting AIMP2-DX2 in lung cancer.
One-pot synthesis of 2-bromo-6-hydroxybenzofurans and their applications in the divergent synthesis of bioactive benzofurans are successfully established.
) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure−activity relationships and computational studies for protein−protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.
2-Aryl/alkylbenzofurans, which constitute an important subclass
of naturally occurring lignans and neolignans, have attracted extensive
synthetic efforts due to their useful biological activities and significant
pharmacological potential. Herein, we report a general and efficient
approach to divergent 2-arylbenzofurans through a one-pot synthesis
of versatile 2-bromobenzofurans as key intermediates. Using this approach,
the first total synthesis of a series of trisubstituted and tetrasubstituted
benzofurans bearing the hydroxyethyl unit, including the natural compounds
isolated from Lavandula agustifolia (1–3) and their non-natural derivatives (4–8), was accomplished. We also report
a modified synthesis of ailanthoidol, homoegonol, and egonol that
enables the divergent synthesis of their derivatives for future exploration.
Among these, the representative phenolic natural compound 2 and its derivatives 7 and 5 induced apoptotic
cell death related poly(ADP-ribose) polymerase (PARP) cleavage in
MCF74, A549, PC3, HepG2, and Hep3B cancer cell lines. Additionally,
the tumor suppressor protein p53 was also induced in p53 wild type
cancer cells.
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