The Use of Stilbene Scaffold in Medicinal Chemistry and Multi- Target Drug Design

Abstract

The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

“…Finally, it is proposed that the use of antioxidants and anti‐inflammatories as an alternative treatment for metabolic disorders such as overweight, obesity, and T2DM would represent another option to improve neuronal and cognitive impairment in AD (Giacomini, Rupiani, Guidotti, Recanatini, & Roberti, ; Marlatt, Lucassen, Perry, Smith, & Zhu, ). Epidemiological studies have shown that people with Obesity and T2DM who received a chronic treatment with antioxidants or anti‐inflammatories, besides showing a greater sensitivity to insulin and low glucose levels, are also at low risk for developing cognitive damage or AD (Walker & Harrison, ).…”

Resveratrol derivatives as a pharmacological tool

“…The goal has been to produce compounds more powerful and/or more convenient than plant‐made stilbenes or endowed with new pharmaceutical properties. This work cannot be covered here for reasons of space, but we refer the interested reader to a few original papers and reviews …”

Design, Synthesis and Biological Activities of New Pyrazole Derivatives Possessing Both Coxib and Combretastatins Pharmacophores

“…Moreover, five new coxib-hybrided compounds (en-tries 2, 5, 10,11,20) show their inhibition rate of cell growth against HT-29 cells from three to six folds stronger than celecoxib and compound 6cb (entry 10) possesses IC 50 around 10 μM. Generally, the presence of a nitrogen-bearing group together with a halogenbearing group at para-position of both adjacent phenyl rings (entries 2, 6, 7, 8, 11) contribute to the increase of cytotoxicity while para-halogen-bearing group, para-hydroxy group or even no substituted group at para-position (entries 2-11) may play a better role in cytotoxic activity than para-methyl group in case of celecoxib or para-methoxy group (entries 17,18,19,21). Adding one more non substituted phenyl ring to coxib pharmacophore may play an important role in determining a better cytotoxicity against MCF-7 and HT-29 cells (entries 2-11).…”

“…KUNTZE (Combretaceae), are also characterized by the presence of 1,2-diphenylethylene nucleus and have become of particular interest to chemists and biologists because of their wide range of biological activities including anti-inflammatory, anticancer, antiviral, antioxidant and more recently neuroprotective effects (Figure 1). [17] Combretastatin A-4 (CA-4) exhibits strong antitubulin activity by binding to the colchicine binding site of tubulin. [18] It exhibits potent cytotoxicity against a broad spectrum of human cancer lines.…”

“…The multiple biological activities and the structural simplicity of combretastatin derivatives make them suitable for the design of hybrid drugs and many example of stilbene based hybrid compounds as potential agents in the fields of cancer, anti-inflammation and other relevant diseases have been reported in the last decade. [17] We now report the synthesis and biological activities of novel aryl-substituted pyrazole derivatives mimicking cis-diphenylethylene scaffold of celecoxib as well as CA-4. The cytotoxic effects of these compounds against three human cancer cell lines HT-29, Hep-G2, MCF-7 as well as the inhibition of NO production using lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells were studied.…”