The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the 3-carbonyl linker. The SAR information revealed that the methoxy group of the B ring could be replaced with an electron-donating group such as methyl (in compound 9) or N,N-dimethylamino (in compound 13) while retaining both strong cytotoxic and antitubulin activities. The introduction of amide (compounds 30-33) and carbamate (compounds 34-37) functionalities at the N1 position of 8 gave analogues with potent antiproliferative activities. The cytotoxic potency of 8 was improved by replacing the carbonyl group with sulfide (compound 41) or oxygen (compound 43), indicating that the carbonyl moiety is important but not essential. The N,N-dimethylamino derivative 13 not only displayed potent cytotoxicity and antitubulin activity, but also showed a markedly improved physicochemical profile relative to the parent compound.
The present study demonstrates that 1,25(OH) D treatment has the potential to improve diabetic cardiomyopathy in rats and suggests that VD-VDR signaling induces this protective effect against diabetic cardiomyopathy might partly through the PARP1/SIRT1/mTOR pathway.
Obesity is often associated with the risk of chronic inflammation and other metabolic diseases, such as diabetes, cardiovascular disease, and cancer. The composition and activity of the gut microbiota play an important role in this process, affecting a range of physiological processes, such as nutrient absorption and energy metabolism. The active gut microbiota can produce a large number of physiologically active substances during the process of intestinal metabolism and reproduction, including short‐chain/long‐chain fatty acids, secondary bile acids, and tryptophan metabolites with beneficial effects on metabolism, as well as negative metabolites, including trimethylamine N‐oxide, delta‐valerobetaine, and imidazole propionate. How gut microbiota specifically affect and participate in metabolic and immune activities, especially the metabolites directly produced by gut microbiota, has attracted extensive attention. So far, some animal and human studies have shown that gut microbiota metabolites are correlated with host obesity, energy metabolism, and inflammation. Some pathways and mechanisms are slowly being discovered. Here, we will focus on the important metabolites of gut microbiota (beneficial and negative), and review their roles and mechanisms in obesity and related metabolic diseases, hoping to provide a new perspective for the treatment and remission of obesity and other metabolic diseases from the perspective of metabolites.
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