Current Medicinal Chemistry - Volume 30, Issue 10, 2023

It is a common practice to take into consideration age, diabetes, smoking, treated and untreated systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol for the prediction of atherosclerosis and stroke. There are, however, ultrasound markers in use for the assessment of atherosclerosis and the evaluation of stroke risk. Two areas of investigation are of interest: the carotid artery and the intracranial arterial circulation. Again, within the domain of the carotid artery, two ultrasonic markers have attracted our attention: intima media thickness of the carotid artery and the presence of carotid plaque with its various focal characteristics. In the domain of intracranial circulation, the presence of arterial stenosis and the recruitment of collaterals are considered significant ultrasonic markers for the above-mentioned purpose. On the other hand, a series of serum, urine, and tissue biomarkers are found to be related to atherosclerotic disease. Future studies might address the issue of whether the addition of proven ultrasonic carotid indices to the aforementioned serum, urine, and tissue biomarkers could provide the vascular specialist with a better assessment of the atherosclerotic load and solidify their position as surrogate markers for the evaluation of atherosclerosis and stroke risk.

Sydnones are among the most well-known mesoionic compounds. Since their synthesis in 1935 by Earl and Mecknay, numerous researches have shown that the chemical behavior, physical and biological properties of sydnones make them the most useful compounds in organic chemistry. Sydnones undergo thermal 1,3-dipolar cycloaddition reaction with dipolarophiles (alkynes or alkenes) to give exclusively derivatives containing a pyrazole moiety exhibiting numerous applications, such as pharmaceuticals and agrochemicals. However, the sydnone cycloaddition reaction with alkynes requires harsh conditions, like high temperatures and long reaction times, giving poor regioselectivity to the resulting products. To overcome these constraints, new reactions named CuSAC (Copper- Catalyzed Sydnone-Alkyne Cycloaddition) and SPSAC (Strain-Promoted Sydnone- Alkyne Cycloaddition) have been developed, leading to pyrazoles with interesting constant kinetics.

Among the aromatic heterocycle rings, pyrazole –a five-membered ring with two adjacent nitrogen atoms in its structure has been postulated as a potent candidate in the pharmacological context. This moiety is an interesting therapeutic target covering a broad spectrum of biological activities due to its presence in many natural substances. Hence, the potential of the pyrazole derivatives as antitumor agents has been explored in many investigations, showing promising results in some cases. In this sense, breast cancer, which is already the leading cause of cancer mortality in women in some countries, has been the topic selected for this review, which covers a range of different research from the earliest studies published in 2003 to the most recent ones in 2021.

Background: Trk gene fusions are an important driver in the development of cancers, including secretory breast cancer and infantile congenital sarcoma. Since the first-generation of small molecule Trk inhibitors (Larotrectinib and Entrectinib) came to market, research on small molecule TRK inhibitors, especially second-generation inhibitors that break through the resistance problem, has developed rapidly. Therefore, this article focuses on the research progress of first-generation drugs and second-generation drugs that break through drug resistance. Methods: We used the database to search for relevant and cutting-edge documents, and then filtered and selected them based on the content. The appropriate articles were analyzed and classified, and finally, the article was written according to the topics. Results: The phenomenon of Trk protein fusion and its relation to tumors are described, followed by an explanation of the composition and signaling pathways of Trk kinases. The representative Trk inhibitors and the development of novel Trk inhibitors are classified according to whether they overcome drug resistance problems. Conclusion: This paper provides a theoretical reference for the development of novel inhibitors by introducing and summarizing the representative and novel Trk inhibitors that break through the drug resistance problem.

Background: Mouse Double Minute 2 Homolog (MDM2) oncogenic protein is the principal cellular antagonist of the p53 tumor suppressor gene. Restoration of p53 activity by inhibiting the MDM2-P53 interactions at the molecular level has become the cornerstone of cancer research due to its promising anticancer effects. Natural medicinal products possess various chemical structures and represent an essential source for drug discovery. α-Mangostin (AM) and gambogic acid (G250) are plant-derived compounds that showed inhibitory effects on MDM2-P53 interactions in vitro and in vivo. Methods: Despite the many clinical studies which performed deeper insight about the molecular understanding of the structural mechanisms exhibited by α-Mangostin and Gambogic acid-binding to MDM2 remains critical. In this study, comparative molecular dynamics simulations were performed for each Apo and bound p53 and MDM2 proteins to shed light on the MDM2-p53 interactions and get a better understanding of the inhibition mechanisms. Results: Results revealed atomistic interaction of AM and G250 within the MDM2-p53 interaction cleft. Both compounds mediate the interaction between the α-helix motifs of the p53 amino-terminal domain, which caused a significant separation between orthogonally opposed residues, specifically Lys8 and Gly47 residues of the p53 and MDM2, respectively. Contrasting changes in magnitudes were observed in per-residue fluctuation on AM and G250 (~0.04 nm and ~2.3 nm, respectively). The Radius of gyration (~0.03 nm and 0.04 nm, respectively), C-alpha deviations (~0.06 nm and 0.1 nm, respectively). The phenolic group of AM was found to establish hydrogen interactions with Glu28 and His96 residues of MDM2. The trioxahexacyclo-ring of G250 also forms hydrogen bond interactions with Lys51 and Leu26 residues of MDM2. Conclusion: Utilizing the information provided on the inhibitory binding mode adopted by each compound in this study may further assist in the tailored designs for cancer therapeutics.