Current Medicinal Chemistry - Volume 29, Issue 41, 2022

The most relevant lipase-catalyzed strategies for the synthesis of pharmaceutically important cyclic and acyclic α-, β- and γ-amino carboxylic acid enantiomers through hydrolysis of the corresponding amino carboxylic esters and lactams, over the last decade are overviewed. A brief Introduction part deals with the importance and synthesis of enantiomeric amino acids, and formulates the objectives of the actual work. The strategies are presented in the Main Text, in chronological order, classified as kinetic, dynamic kinetic and sequential kinetic resolution. Mechanistic information of the enzymatic transformations is also available at the end of this overview. The pharmacological importance of the enantiomeric amino acids is given next to their synthesis, in the Main Text, and it is also illustrated in the Conclusions and Outlook sections.

The C-X3-C motif chemokine ligand (CX3CL)1 (also known as Fractalkine) and its receptor CX3CR1 (also known as G-protein coupled receptor 13) are expressed on the membranes of many different cells such as epithelial cells, dendritic cells, smooth muscle cells, and neurons. CX3CR1 is primarily expressed on monocytes, macrophages, dendritic cells, T cells, and natural killer cells. The binding of CX3CL1 to CX3CR1 induces the activation of heterotrimeric G proteins associated with this receptor. In addition, it triggers the signal pathways of MAPK and AKT, which play essential roles in tumour biology. Mechanistically, the CX3CL1-CX3CR1 axis has an antitumour role by recruiting antitumoural immune cells such as NK cells and T cells into the tumour microenvironment to control tumour growth. On the other hand, accumulated evidence indicates that the CX3CL1-CX3CR1 axis also activates a pro-tumoral response. This review will focus on the unique structural biology features of CX3CL1 and CX3CR1, their interactions in tumour inflammatory response, and antitumour effects, which highlights possible potential therapeutic targets.

Background and Aims: Current methods (highly sensitive and ultra-sensitive) of cardiospecific troponins detection have enabled early diagnosis of myocardial infarction (MI) and selection of optimal treatment tactics for patients early from admission. The use of these methods in real clinical practice helps to choose the most optimal treatment tactics for patients in the early stages after admission, and this significantly improved the further prognosis of patients suffering from MI. However, there are a number of problems that arise when using highly sensitive or ultra-sensitive methods for determining cardiospecific troponins: frequent and unexplained increases in serum levels of cardiospecific troponins in a number of pathological conditions unrelated to MI; insufficient knowledge and understanding of the mechanisms of release and increase in the levels of cardiospecific troponins; poorly understood features and mechanisms of circulation and elimination of cardiospecific troponins; the presence of conflicting information about the influence of several factors (gender, age and circadian characteristics) on the levels of cardiospecific troponins in blood serum; undisclosed diagnostic potential of cardiospecific troponins in non-invasive human biological fluids. These problems cause great difficulties and increase the risk of errors in the differential diagnosis of MI, and also do not allow to fully unlock the diagnostic potential of cardiospecific troponins. In general, these problems are associated with a lack of understanding of the fundamental mechanisms of the metabolism of cardiospecific troponins. The main purpose of this narrative review is to summarize and provide detailed information about the metabolism of cardiospecific troponins and to discuss the potential impact of metabolic features on the diagnostic value of cardiospecific troponins and their diagnostic capabilities. Materials and Methods: This narrative review is based on the analysis of publications in the Medline, PubMed, and Embase databases. The terms “cardiac troponins”, “troponin T”, and “troponin I” in combination with “mechanisms of increase”, “mechanisms of release”, “circulation”, “proteolytic cleavage”, “elimination”, “circadian rhythms”, “saliva”, and “urine” were used to search publications. Results: It has been reported that the metabolic features (mechanisms of release, circulation, and elimination) of cardiospecific troponins may have an important influence on the diagnostic value of cardiospecific troponins in a number of physiological and pathological conditions that cause cardiomyocyte damage. The main mechanisms of cardiac troponin release are: cardiomyocyte apoptosis; myocardial cell regeneration and renewal; increased cell membrane permeability; release of troponins by vesicular transport; increased proteolytic degradation of cardiospecific troponin molecules within the cell which may facilitate their release from intact myocardial cells or in the initial phase of those pathological conditions that increase the activity of enzymes that degrade cardiospecific troponins. Besides, the formation of small fragments (troponin molecules) may facilitate their penetration into other body fluids such as urine and/or oral fluid which may provide researchers and practitioners with a new diagnostic opportunity. It should be noted that in addition to release mechanisms, cardiospecific troponin elimination mechanisms may play an important diagnostic role. The contribution of release and elimination mechanisms to different pathologies may differ significantly. Circadian rhythms of cardiospecific troponins may be associated with fluctuations in the activity of those organ systems which influence the mechanisms of cardiospecific troponin release or elimination. Such major systems include: neuroendocrine, urinary, and hemostasis. Conclusion: Cardiospecific troponins metabolism has an important influence on diagnostic value and diagnostic capabilities. Further study of the features of cardiac troponin metabolism (mechanisms of release, circulation and elimination) is required to improve diagnosis and differential diagnosis of diseases causing cardiomyocyte damage. The data on the influence of circadian rhythms of cardiospecific troponins on the diagnostic value and the possibility of determining cardiospecific troponins in body fluids that can be obtained by noninvasive methods are very interesting. However, so far this information and valuable capabilities have not been applied in clinical practice because of the paucity of studies conducted.

In recent years, the incidence of erectile dysfunction (ED) has continued to rise worldwide. Since pharmacotherapy is still the most common and effective method for the treatment of ED at present, many methods and drugs have been designed or developed for the treatment of ED. Oral phosphodiesterase-5 inhibitors and androgen supplement therapy are currently the common therapeutics for ED; however, some patients have poor responses to these drugs because of the multiple pathogenic mechanisms of ED. Researchers are trying to find other treatment ways. On the one hand, many new strategies and concepts, such as targeted therapy, are also integrated into clinical or preclinical research; on the other hand, some combined therapies that have synergistic effects with a reduced dose of a single drug and less adverse effects are also developed. This review article summarized the efficacy of the latest first-line, second-line drugs and adjuvant therapies for the treatment of ED, as well as the application of comprehensive treatments, which will help doctors not only deeply understand the mechanism of ED but select the suitable therapeutics for those patients.

Pyranopyrazoles are bicyclic nitrogen-containing heterocycles having broadspectrum bioactivities, which may act as anti-cancer, anti-inflammatory, antibacterial, antifungal, insecticidal and molluscicidal agents. Pyranopyrazoles have become an attractive scaffold for the discovery of new drugs due to the diverse range of bioactivities associated with this nucleus. In this review, we have focused on the medicinal importance of pyranopyrazole derivatives and highlighted different routes for the synthesis of pyranopyrazole derivatives using inexpensive and commonly available starting materials.