Current Medicinal Chemistry - Volume 30, Issue 14, 2023

Background: PROTACs is an emerging technique that addresses the disease causing proteins by targeting protein degradation. PROTACs molecules are bifunctional small molecules that simultaneously bind to the protein of interest (POIs) and an E3 ligase followed by ubiquitination and degradation of the protein of interest by the proteasome. Objective: PROTACs technology offers many advantages over classical inhibition such as PROTACs molecules can target intracellular proteins regardless of their function and have good tissue distribution. They are capable to target mutated and overexpressed proteins, thus potent molecules with the high degradation selectivity can be designed. Moreover, PROTACs molecules can target the undruggable proteome which makes up almost 85% of human proteins. Several PROTACs-based compounds have exhibited high therapeutic potency and some of them are currently under clinical trials. Methods: Current article gives a comprehensive overview of the current development of PROTACs-based anticancer compounds along with the structure-activity relationship of the reported molecules. Results: The development of PROTACs-based compounds and related research regarding medicinal chemistry is one of the most active and hot topics for research. Conclusion: It is believed that the current review article can be helpful to understand the logical design of more efficacious PROTACs-based molecules with less toxicity and more selectivity.

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia and associated with multiple organ systems complications. The incidence and prevalence of diabetes are increasing in an epidemic proportion worldwide. In addition to environmental factors, some epigenetic and post-translational modifications have critical roles in the pathogenesis of diabetes and its complications. Reversible covalent modification such as SUMOylation by SUMO (Small Ubiquitin-like Modifier) has emerged as a new mechanism that affects the dynamic regulation of proteins. In this review, we initially focus on the function of SUMO and SUMOylation. Subsequently, we assess the potential effects of this process in the pathogenesis of type 1 and 2 diabetes mellitus.

Ferroptosis is a recently discovered type of cell death caused by the accumulation of iron-dependent lipid peroxides and reactive oxygen species that differs significantly from other cell death pathways such as apoptosis, necrosis, and autophagy. Ferroptosis is essential in developing and treating ischemia-reperfusion injury, neurological diseases, cancer, and other diseases. The ferroptosis mechanism, which can be induced by reagents like erastin and glutamate, and suppressed by antioxidants such as vitamin E and deferoxamine (DFO) chelators, can be regulated at the epigenetic, transcriptional, post-transcriptional, and post-translational levels. A recent study has determined many non-coding RNAs (lncRNA, miRNA, circRNA) that modulate ferroptotic cell death in cancer cells. Furthermore, some anti-cancer drugs (Sorafenib, Sulfasalazine, Acetominofen, Lanperisone, etc.) used in pre-clinical and clinical applications have been shown to induce ferroptosis in various cancer types. However, in addition to the studies in the literature, it is necessary to define novel molecules & non-coding RNAs and determine their effects on the ferroptosis mechanism. Thus, it will be possible to develop effective and safe treatment options.

Background: Insulin-like growth factor (IGF-1) is associated with breast cancer in menopausal women. Naturally occurring biomolecules found in common dietary protocols, such as flavonoids, play a key role in the inhibition and treatment of cancer. In-vitro/in-vivo studies showed that treatment involving flavonoids led to a reduced risk of breast cancer due to the decrease of IGF-1 level in addition to an increased insulin-like growth factor binding protein (IGFBP)-3. However, clinical studies did not show conclusive results in this regard because they are contradictory. Objective: The aim of the present study was to find the effect of flavonoids on IGF-1 and IGFBP-3 and the incidence of breast cancer. Methods: This systematic review was performed using PubMed, Scopus, ISI Web of Science, and EMBASE databases to collect results about the clinical use of flavonoids and their effects on breast cancer. After eliminating duplicate articles, the title and abstract of the remaining articles were examined in thematic communication, and related clinical articles were selected and studied based on inclusion criteria. The data were extracted from each article, and then statistical analysis was subsequently carried out by Comprehensive Meta-Analysis. Results: The results showed that the effect of flavonoids on changes in IGF1 and IGFBP-3 was not statistically significant. No significant heterogeneity was detected across the studies. Pooled effect size also indicated that the mean change was not statistically significant. No significant heterogeneity was detected across the studies. There was no evidence of publication bias for IGF1 and IGFBP-3. Conclusion: This meta-analysis study suggests that flavonoid supplementations have no significant effect on IGF-1 and IGFBP-3, and a high soy diet has beneficial effects on IGF system components, which might be useful in breast cancer.

Introduction: Opioid Free Anesthesia (OFA) is a relatively new technique that has been questioned due to the lack of evidence regarding its benefit-risk balance. Methods: Four international databases were searched for clinical trials comparing OFA with opioid based anesthesia. The primary outcome was pain control and the secondary included postoperative nausea and vomiting (PONV), gastrointestinal recovery, respiratory depression, urinary retention, length of hospital stay, surgical complications, number of patients with cessation of the intervention and other side effects. Results: Pain was better controlled in the OFA group in all the measurements made (VAS 1h: Md = -0.81, CI95% = -0.48- -1.14, VAS 24h: Md = -1.25, CI95% =-2.41- -0.1, VAS >24h: Md = -1.36, CI95% = -1.73- -1). In the opioid group there was an increase in the risk of nausea (RR=2.69, CI95% = 2-3.61) and vomiting (RR = 3.99, CI95% = 2.06-7.74), whilst in the OFA group, there was an increased risk of bradycardia (RR= 1.62, CI95% = 1.02-2.57). The rest of the variables showed no differences between groups or could not be analyzed. Conclusion: There is a clear benefit of OFA in pain control and PONV, but there is also a higher risk of bradycardia. This technique should be considered in patients with a special risk of difficult postoperative pain control or PONV. However, the best drug combination to perform OFA is still unknown, as well as the type of patient that benefits more with less risk.