Abstract
Diabetes mellitus (DM) represents a complex and multifactorial disease that causes metabolic disorders with acute and long-term serious complications. The onset of DM, with over 90% of cases of diabetes classified as type 2, implies several metabolic dysfunctions leading to consider DM a worldwide health problem. In this frame, protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) are two emerging targets involved in the development of type 2 diabetes mellitus (T2DM) and its chronic complications. Herein, we employed a marine-derived dual type inhibitor of these enzymes, phosphoeleganin, as chemical starting point to perform a fragment-based process in search for new inhibitors. Phosphoeleganin was both disassembled by its oxidative cleavage and used as model structure for the synthesis of a small library of functionalized derivatives as rationally designed analogues. Pharmacological screening supported by in silico docking analysis outlined the mechanism of action against PTP1B exerted by a phosphorylated fragment and a synthetic simplified analogue, which represent the most potent inhibitors in the library.
Highlights
In addition to the continued progress toward understanding the key cellular and molecular processes involved in the pathobiology of a given disease and, validating suitable drug targets, the major problem in drug discovery remains the availability of novel chemical scaffolds
We have demonstrated that phosphoeleganin (1), a phosphorylated poliketide isolated from the Mediterranean ascidian Sidnyum elegans, is able to inhibit both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), acting as an insulin-sensitizing agent [12]
Pharmacological screening of the obtained fragments library highlighted that all compounds in the series significantly lost the activity against
Summary
In addition to the continued progress toward understanding the key cellular and molecular processes involved in the pathobiology of a given disease and, validating suitable drug targets, the major problem in drug discovery remains the availability of novel chemical scaffolds. Large chemical libraries with associated high chemical diversity are needed to identify new lead compounds; in the current genomic era, in which tens of thousands of potential drug targets have been identified, the challenge of success lies in the number of small molecules that can be used as their modulators. Large and focused molecules libraries can be obtained by combinatorial chemistry approaches, in which chemical structures generated by computer software are prepared through systematic and repetitive linkage of various “building blocks”. An advantageous alternative to combinatorial chemistry as a resource of chemical diversity are Natural Products (NPs), which offer favourable features for drug discovery, first their huge scaffold diversity and structure complexity. 65% of clinical drugs were derived from nature or they have been designed employing NP scaffolds as inspiring tools [1,2].
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