Deciphering the signaling mechanisms of ß-arrestin1 and ß-arrestin2 in regulation of cancer cell cycle and metastasis.

ß-Arrestins are ubiquitously expressed intracellular proteins with many functions which interact directly and indirectly with a wide number of cellular partners and mediate downstream signaling. Originally, ß-arrestins were identified for their contribution to GPCR desensitization to agonist-mediated activation, followed by receptor endocytosis and ubiquitylation. However, current investigations have now recognized that in addition to GPCR arresting (hence the name arrestin). ß-Arrestins are adaptor proteins that control the recruitment, activation, and scaffolding of numerous cytoplasmic signaling complexes and assist in G-protein receptor signaling, thus bringing them into close proximity. They have participated in various cellular processes such as cell proliferation, migration, apoptosis, and transcription via canonical and noncanonical pathways. Despite their significant recognition in several physiological processes, these activities are also involved in the onset and progression of various cancers. This review delivers a concise overview of the role of ß-arrestins with a primary emphasis on the signaling processes which underlie the mechanism of ß-arrestins in the onset of cancer. Understanding these processes has important implications for understanding the therapeutic intervention and treatment of cancer in the future.

Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90).

A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.

Cycloaddition of Spiroepoxycyclohexa-2,4-dienones, Radical Cyclization and 1,3-Acyl Shift in Excited State: Aromatics to Sterpuren-4-one.

A stereoselective route to sterpuren-4-one from a simple aromatic precursor is presented. Oxidative dearomatization, π4s + π2s cycloaddition of 6,6-spiroepoxycyclohexa-2,4-dienones with ethyl acrylate, radical cyclization and 1,3-acyl shift in excited state are the important aspects of our approach. An interesting effect of a remote substituent on radical cyclization has also been presented.

Discovery of indazole inhibitors for heat shock protein 90 as anti-cancer agents.

A series of indazole analogs, derived from the B,C-ring-truncated scaffold of deguelin, were designed to function as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antitumor agents against HER2-positive breast cancer. Among the synthesized compounds, compound 12d exhibited substantial inhibitory effects in trastuzumab-sensitive (BT474) and trastuzumab-resistant (JIMT-1) breast cancer cells, with IC50 values of 6.86 and 4.42 µM, respectively. Notably, compound 12d exhibited no cytotoxicity in normal cells. Compound 12d markedly downregulated the expression of the major HSP90 client proteins in both cell types, attributing its cytotoxicity to the destabilization and inactivation of HSP90 client proteins. Molecular docking studies using the homology model of an HSP90 homodimer demonstrated that inhibitor 12d fit nicely into the C-terminal domain, boasting a higher electrostatic complementary score than ATP. In vivo pharmacokinetic study indicated the high oral bioavailability of compound 12 d at F = 66.9 %, while toxicological studies indicated its negligible impact on hERG channels and CYP isozymes. Genotoxicity tests further confirmed its safety profile. The findings collectively position compound 12d as a promising candidate for further development as an antitumor agent against HER2-positive breast cancer.

Total Synthesis of Natural Products using Gold Catalysis.

Gold catalysis is an extremely enthusiastic field of investigation in the catalysis area. The development of alternative, highly inventive, precompetitive techniques based on gold catalysis has paved the way for executing a broad spectrum of chemical transformations from uncomplicated starting materials. The total synthesis of natural products is a complex and more complicated task. An amalgamation of natural product synthesis through gold-catalysis has been a thought-provoking job. The protocol has solved several problems related to the synthesis of numerous complicated natural products. Thus, this review has outlined some of the most notable benchmarks from the last seven years (2015-2021) on gold catalysis and their application in the total synthesis of numerous natural products. The strategy acquired by the authors to accomplish the total synthesis will be elaborately discussed by emphasizing the role of the gold-catalyzed reactions.

Seeking heterocyclic scaffolds as antivirals against dengue virus.

Dengue is one of the most typical viral infection categorized in the Neglected Tropical Diseases (NTDs). It is transmitted via the female Aedes aegypti mosquito to humans and majorly puts risk to the lives of more than half of the world. Recent advancements in medicinal chemistry have led to the design and development of numerous potential heterocyclic scaffolds as antiviral drug candidates for the inhibition of the dengue virus (DENV). Thus, in this review, we have discussed the significance of inhibitory and antiviral activities of nitrogen, oxygen, and mixed (nitrogen-sulfur and nitrogen-oxygen) heterocyclic scaffolds that are published in the last seven years (2016-2022). Furthermore, we have also discussed the probable mechanisms of action and the diverse structure-activity relationships (SARs) of the heterocyclic scaffolds. In addition, this review has elaborately outlined the mechanism of viral infection and the life cycle of DENV in the host cells. The wide set of heterocycles and their SARs will aid in the development of pharmaceuticals that will allow the researchers to synthesize the promising anti-dengue drug candidate in the future.

The recent challenges of highly contagious COVID-19, causing respiratory infections: Symptoms, diagnosis, transmission, possible vaccines, animal models, and immunotherapy.

COVID-19 is highly contagious pathogenic viral infection initiated from Wuhan seafood wholesale market of China on December 2019 and spread rapidly around the whole world due to onward transmission. This recent outbreak of novel coronavirus (CoV) was believed to be originated from bats and causing respiratory infections such as common cold, dry cough, fever, headache, dyspnea, pneumonia, and finally Severe Acute Respiratory Syndrome (SARS) in humans. For this widespread zoonotic virus, human-to-human transmission has resulted in nearly 83 lakh cases in 213 countries and territories with 4,50,686 deaths as on 19 June 2020. This review presents a report on the origin, transmission, symptoms, diagnosis, possible vaccines, animal models, and immunotherapy for this novel virus and will provide ample references for the researchers toward the ongoing development of therapeutic agents and vaccines and also preventing the spread of this disease.

Sustainable and Efficient Route for the Regeneration of Carbonyl Compounds from Oximes Using Aqueous Extract of Sapindus laurifolia under Microwave Radiation.

The synthesis of organic compounds using aqueous medium has become an indispensable tool for modern chemical synthesis strategies because of its ability to produce pure products with higher yield at ambient temperature. The conversion of oxime group into carbonyl group serves as a key step for several organic syntheses. This article describes the regeneration of carbonyl compounds from the oxime group present in various carbon skeletons using I2 and aqueous extract of Sapindus laurifolia under microwave radiation. A correlation has been established between the critical micellar concentration of saponin extracted from Sapindous laurifolia and the yield percentage of regenerated different carbonyl compounds. An effortless, competent, and environmentally compassionate protocol for the regeneration of carbonyl compound with a high percent of yield in the range 45-95% could be achieved.