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Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived Mks. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with the potential to affect MKL1 function and found that DYRK1A inhibition dramatically enhanced Mk morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal Mks. Mks derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss-of-function studies confirmed MKL1 involvement in this morphogenetic pathway. Expression of Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile Mks., Introduction Human megakaryocytes (Mks) undergo dramatic changes during ontogenic progression from fetal through adult stages. These changes include diminishing proliferation and a concomitant increase in adult-type morphogenesis (1-3). Adult-type morphogenesis [...]

The article discusses the synthesis of thiazole-fused tricyclic quinazolinone alkaloids and their derivatives, focusing on compounds found in traditional Chinese and Indian herbal medicine. The authors describe their synthetic program and the successful synthesis of various thiazole-fused tricyclic quinazolinones. The article provides information on the physical and chemical properties of the synthesized compounds, including melting points, yields, and spectral analysis results. This information can be useful for researchers studying these compounds and their potential applications. [Extracted from the article]

SP 1 sp H NMR (300 MHz, acetone- I d i SB 6 sb ): = 11.66 (s, 1 H, H SB N-H sb ), 8.39 (d, I J i = 8.2 Hz, 1 H, H SB 7 sb ), 8.35 (d, I J i = 2.6 Hz, 1 H, H SB 2 sb ), 8.12 (d, I J i = 8.3 Hz, 1 H, H SB 6 sb ). SP 1 sp H NMR (300 MHz, acetone- I d i SB 6 sb ): = 11.49 (s, 1 H, H SB N-H sb ), 8.78 (d, I J i = 2.3 Hz, 1 H, H SB 5 sb ), 8.46 (d, I J i = 2.3 Hz, 1 H, H SB 7 sb ), 8.30 (d, I J i = 2.8 Hz, 1 H, H SB 2 sb ), 8.17-8.07 (m, 2 H, H SB 10or11 sb ), 8.03-7.94 (m, 2 H, H SB 10or11 sb ). SP 13 sp C NMR (75 MHz, acetone- I d i SB 6 sb ): = 157.11 (d, I J i = 15.3 Hz, C SB 4 sb ), 155.38 (dd, I J i = 263.6, 4.4 Hz, Cq), 150.58 (dd, I J i = 253.0, 4.6 Hz, Cq), 148.32 (Cq), 147.54 (C SB 2 sb ), 121.72 (Cq), 120.75 (d, I J i = 3.6 Hz, Cq), 120.03 (Cq), 120.0-104.00 (m, C SB CF sb ). SP 13 sp C NMR (75 MHz, acetone- I d i SB 6 sb ): = 159.44 (C SB 4 sb ), 155.77 (dd, I J i = 266.4, 19.7 Hz, Cq), 150.08 (dd, I J i = 250.8, 15.1 Hz, Cq), 147.14 (C SB 2 sb ), 146.85-146.21 (m, Cq), 122.57-121.48 (m, Cq), 119.05 (dd, I J i = 18.9, 3.4 Hz, C SB 5 sb ), 118.93-114.64 (m, Cq), 119.00-105.00 (m, C SB CF sb ). SP 13 sp C NMR (75 MHz, acetone- I d i SB 6 sb ): = 159.91 (dt, I J i = 252.3, 5.2 Hz, C SB 6 sb ), 157.63 (d, I J i = 3.8 Hz, C SB 4 sb ), 147.42 (Cq), 146.79 (C SB 2 sb ), 133.10 (d, I J i = 7.3 Hz, Cq), 126.29-125.29 (m, C SB 5,7,8 sb ),, 123.00-105.00 (m, C SB CF sb ). [Extracted from the article]

Removal of the cyano group on the thiazole ring was performed by heating 2-cyanobenzothiazoles B III b and B IV b in HCl (37% in water) for 45 minutes to yield the corresponding carbonitrile-free analogues B IIIa b and B IVa b in yields of 53% and 25%, respectively, respectively. Thus, in the presence of KI, the cyclization of cyanothioformanilide B 3c b led to benzothiazole B VI b (13% yield), together with the corresponding isothiocyanate B 4c b , being the major product in 37% yield (Table 4, entry 1). HRMS (EI SP + sp ): I m i / I z i [M + H] SP + sp calcd for C SB 9 sb H SB 9 sb N SB 2 sb O SB 2 sb S: 209.0385; found: 209.0388. HRMS (EI SP + sp ): I m i / I z i [M + H] SP + sp calcd for C SB 9 sb H SB 9 sb N SB 2 sb O SB 2 sb S: 209.0385; found: 209.0378. [Extracted from the article]

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL., Introduction B cell acute lymphoblastic leukemia (B-ALL) is the most commonly diagnosed pediatric cancer, with incidence peaking between the ages of 2 and 5 years (1). The success of multidrug [...]

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article. [ABSTRACT FROM AUTHOR]

In order to prepare an array of β-cyanoenamine derivatives as potential precursors of heterocyclic systems with pharmaceutical interest, the synthesis of fifteen polyfunctionalized 4 H -chromenes was realized via a microwave-assisted and catalyst-free three-component reaction. Microwave-heated reactions were monitored by Raman spectroscopy, enabling a fast and efficient setting of the process parameters. This study confirms that this monitoring tool may have some limitations linked to homogeneity of reaction medium. This work also investigates the use of some bio-sourced and sustainable solvents currently studied in many works. Ethanol remains the most suitable for this synthesis. [ABSTRACT FROM AUTHOR]

Abstract: Two reactions, HCl addition and the thermal and (or) microwave assisted Diels-Alder condensation, were performed on α-cubebene (1), a vinylcyclopropane-containing tricyclic sesquiterpene. The diene structures originating from these reactions [...]