Search

In this work, we designed a series of new carbohydrate-based coumarin carbonic anhydrase IX inhibitors by using 1,2,3-triazoles as linker. Next, these designed compounds were synthesized by the optimized one-pot click chemistry reaction condition. Subsequently, these target compounds were assayed for the inhibition of three carbonic anhydrase isoforms (CA I, CA II and CA IX). Intriguingly, all the compounds showed better CA IX inhibitory activity than initial coumarin fragments. Among them, compound 10a (IC50: 11 nM) possessed the most potent CA IX inhibitory activity, which was more potent than the reference drug acetazolamide (IC50: 30 nM). Notably, compound 10a showed 3018-fold, 1955-fold selectivity relative to CA I and CA II, respectively. Meanwhile, representative compounds could reduce tumor cell viability and the extracellular acidification in HT-29 and MDA-MB-231 cancer cell lines. Even more interestingly, our target compounds had no apparent cytotoxicity toward MCF-10A cell line. In addition, the in vitro stability assays also indicated our developed compounds possessed good liver microsomal metabolic stabilities and plasma stability. Furthermore, representative compounds revealed relatively low hERG cardiac toxicity and acute toxicity. Furthermore, docking studies were carried out to understand the interactions of our target compounds with the protein target CA IX. Collectively, our results suggest that compound 10a, as a selective CA IX inhibitor, could be an important lead compound for further optimization and development as an anticancer agent. [ABSTRACT FROM AUTHOR]

Epimedium is a classical Chinese herbal medicine, which has been used extensively to treat various diseases, such as sexual dysfunction, osteoporosis, cancer, rheumatoid arthritis, and brain diseases. Flavonoids, such as icariin, baohuoside I, icaritin, and epimedin C, are the main active ingredients with diverse pharmacological activities. Currently, most Epimedium flavonoids are extracted from Epimedium plants, but this method cannot meet the increasing market demand. Biotransformation strategies promised huge potential for increasing the contents of high-value Epimedium flavonoids, which would promote the full use of the Epimedium herb. Complete biosynthesis of major Epimedium flavonoids by microbial cell factories would enable industrial-scale production of Epimedium flavonoids. This review summarizes the structures, pharmacological activities, and biosynthesis pathways in the Epimedium plant, as well as the extraction methods of major Epimedium flavonoids, and advancements in the biotransformation and complete microbial synthesis of Epimedium flavonoids, which would provide valuable insights for future studies on Epimedium herb usage and the production of Epimedium flavonoids. [ABSTRACT FROM AUTHOR]

A series of new carbohydrate-based sulphonamide derivatives were designed, synthesised by employing the so-call 'sugar-tail' approach. The compounds were evaluated in vitro against a panel of CAs. Compared to their parent compound p-sulfamoylbenzoic acid, these compounds showed nearly 100-fold improvement in their binding affinities against hCA II in vitro. All of compounds showed great water solubility and the pH value of their water solutions of compounds is 7.0. Such properties are advantageous to make them much less irritating to the eye when applied topical glaucomatous drugs, compared to the relatively highly acidic dorzolamide preparations (pH 5.5). Notably, compounds 7d, 7 g, 7 h demonstrated to topically lower intraocular pressure (IOP) in glaucomatous animals better than brinzolamide when applied as a 1% solution directly into the eye. Low cytotoxicity on human cornea epithelial cell was observed in the tested concentrations by the MTT assay. [ABSTRACT FROM AUTHOR]

• Sugar-tail approach was employed to design novel CA IX inhibitors. • Compound 12g (IC 50 of 7 nM) was more effective than the reference drug acetazolamide. • Most of compounds exhibited better antitumor activity under hypoxic conditions. • Representative compounds restored 20%-35% level of the cytotoxic efficiency of doxorubicin. • Docking showed sugar-tail of compound 12g could interact with hydrophilic pocket of CA IX. A series of novel carbohydrate-based sulfonamides were designed and synthesized by the sugar-tail approach. The classical aromatic sulfonamide pharmacophore (ArSO 2 NH 2) was directly linked to a hydrophilic sugar-tail moiety through a rigid 1, 2, 3-triazole linker by the click chemistry reaction. The inhibitory activity against three carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I, hCA II and hCA IX) of all new compounds so designed were investigated in vitro and efficient inhibition against all three CA isoforms, especially the tumor-associated hCA IX, were observed. These glycoconjugate sulfonamide derivatives displayed better inhibitory efficacy in comparison with the starting segments (SA and p -hydroxybenzene sulfonamide). In particular, compound 12g was found to be the most effective and rather selective inhibitor of hCA IX with inhibitory constant (IC 50) value of 7 nM, being four times more potent than the clinical used agent acetazolamide (AAZ) (IC 50 = 30 nM). Meanwhile, almost all compounds showed moderate antiproliferative activities against two cancer cell lines (HT-29 and MDA-MB-231) in both hypoxic and normoxic conditions while compound 12g also exhibited the most prominent antitumor activity. Furthermore, evident recovery (20–35% reduction of IC 50 values) of cytotoxic efficiency of doxorubicin with the combination of compounds 12d , 12g and 22d as CAIs were detected on MDA-MB-231 cell line under hypoxic environment. In addition, docking studies revealed that the sugar-tail fragment of the target compounds participated in interactions with hydrophilic subpocket at the surface of hCA IX active site and supported the CA IX inhibitory activities of carbohydrate-based sulfonamide derivatives. [ABSTRACT FROM AUTHOR]