Genetic Deletion of Trace-Amine Associated Receptor 9 (TAAR9) in Rats Leads to Decreased Blood Cholesterol Levels.

In the last two decades, interest has grown significantly in the investigation of the role of trace amines and their receptors in mammalian physiology and pathology. Trace amine-associated receptor 9 (TAAR9) is one of the least studied members of this receptor family with unidentified endogenous ligands and an unknown role in the central nervous system and periphery. In this study, we generated two new TAAR9 knockout (TAAR9-KO) rat strains by CRISPR-Cas9 technology as in vivo models to evaluate the role of TAAR9 in mammalian physiology. In these mutant rats, we performed a comparative analysis of a number of hematological and biochemical parameters in the blood. Particularly, we carried out a complete blood count, erythrocyte osmotic fragility test, and screening of a panel of basic biochemical parameters. No significant alterations in any of the hematological and most biochemical parameters were found between mutant and WT rats. However, biochemical studies revealed a significant decrease in total and low-density lipoprotein cholesterol levels in the blood of both strains of TAAR9-KO rats. Such role of TAAR9 in cholesterol regulation not only brings a new understanding of mechanisms and biological pathways of lipid exchange but also provides a new potential drug target for disorders involving cholesterol-related pathology, such as atherosclerosis.

Synthesis and in vitro Biological Evaluation of Novel Thymidine Analogs Containing 1H-1,2,3-Triazolyl, 1H-Tetrazolyl, and 2H-Tetrazolyl Fragments.

3'-Azidothymidine (AZT) reacts with 1-propargyl-5-R-1H- and 2-propargyl-5-R-2H-tetrazoles (R = H, Me, CH2COOEt, CH2CON(CH3)2, Ph, 2-CH3-C6H4, or 4-NO2-C6H4) via the Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition to give 3'-modified thymidine analogs incorporating 1H-1,2,3-triazolyl, 1H-, and 2H-tetrazolyl fragments in 41-76% yield. The structures of the obtained compounds have been elucidated by means of HRESI+-MS, 1H and 13 C{1H} NMR, and single crystal X-ray diffraction {for 3'-[4-(1H-5-N,N-dimethylaminocarbonylmethyltetrazol-1-yl)-1H-1,2,3-triazol-1-yl]thymidine 10d}. In vitro biological evaluation of the prepared compounds has been performed; they have exhibited low activity against phenotypic HIV-1899A. Moderate anti-influenza activity against influenza virus A/Puerto Rico/8/34 (H1N1) strain has been observed in the cases of 3'-(4-(1H-tetrazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 10a (IC50 39.6 µg/mL), 3'-(4-(2H-5-ethoxycarbonyltetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11c (IC50 31.6 µg/mL), and 3'-(4-(2H-5-(4-nitrophenyl)-tetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11g (IC50 46.4 µg/mL). The tested compounds possess very low cytotoxicity towards MDCK and MT4 cells as well as tumor human cervical carcinoma HeLa and promyelocytic leukemia HL-60 cells.

Tetrazole Derivatives as Promising Anticancer Agents.

Tetrazole cycle is a promising pharmacophore fragment frequently used in the development of novel drugs. This moiety is a stable, practically non-metabolized bioisosteric analog of carboxylic, cis-amide, and other functional groups. Over recent 10-15 years, various isomeric forms of tetrazole (NH-unsubstituted, 1H-1- substituted, and 2H-2-substituted tetrazoles) have been successfully used in the design of promising anticancer drugs. Coordination compounds of transition metals containing tetrazoles as ligands, semisynthetic tetrazolyl derivatives of natural compounds (biogenic acids, peptides, steroids, combretastatin, etc.), 5-oxo and 5- thiotetrazoles, and some other related compounds have been recognized as promising antineoplastic agents. This review presents a comprehensive analysis of modern approaches to synthesis of these tetrazole derivatives as well as their biological (anticancer) properties. The most promising structure types of tetrazoles to be used as anticancer agents have been picked out.