Induced pluripotent stem cell (iPSC)-based technologies offer an unprecedented opportunity to perform highthroughput screening of novel drugs for neurological and neurodegenerative diseases. Such screenings require a robust and scalable method for generating large numbers of mature, differentiated neuronal cells. Currently available methods based on differentiation of embryoid bodies (EBs) or directed differentiation of adherent culture systems are either expensive or are not scalable. We developed a protocol for large-scale generation of neuronal stem cells (NSCs)/early neural progenitor cells (eNPCs) and their differentiation into neurons. Our scalable protocol allows robust and cost-effective generation of NSCs/eNPCs from iPSCs. Following culture in neurobasal medium supplemented with B27 and BDNF, NSCs/ eNPCs differentiate predominantly into vesicular glutamate transporter 1 (VGLUT1) positive neurons. Targeted mass spectrometry analysis demonstrates that iPSC-derived neurons express ligand-gated channels and other synaptic proteins and whole-cell patch-clamp experiments indicate that these channels are functional. The robust and cost-effective differentiation protocol described here for large-scale generation of NSCs/eNPCs and their differentiation into neurons paves the way for automated high-throughput screening of drugs for neurological and neurodegenerative diseases.
The Amaryllidaceae alkaloid trans-dihydrolycoricidine 7 and three analogues 8−10 were produced via asymmetric chemical synthesis. Alkaloid 7 proved superior to acyclovir, the current standard for herpes simplex virus, type 1 (HSV-1) infection. Compound 7 potently inhibited lytic HSV-1 infection, significantly reduced HSV-1 reactivation, and more potently inhibited varicella zoster virus (VZV) lytic infection. A configurationally defined (3R)-secondary alcohol at C3 proved crucial for efficacious inhibition of lytic HSV-1 infection. KEYWORDS: Herpesvirus, HSV-1, varicella zoster, stem cells, Amaryllidaceae, alkaloid H erpes simplex virus, type 1 (HSV-1) is a ubiquitous DNA virus from the Herpesviridae family that causes substantial human morbidity and mortality. 1 With seropositivity rates exceeding 70% in elders, it causes recurrent cold sores, corneal infection, blindness, and, rarely, encephalitis. 1 It establishes latent infection in sensory neurons that is refractory to clearance, producing an intractable lifelong reservoir that cycles with lytic infections. Though acute HSV-1 infection is readily treatable with nontoxic nucleoside analogues such as acyclovir (ACV), no drug successfully eliminates the latent infection. In addition, growing ACV drug resistance has further fueled the search for novel antivirals. 2 Plants of the Amaryllidaceae family produce numerous structurally diverse, biologically active alkaloids. 3,4 In particular, alkaloids of the lycorane subclass including lycorine 1, pseudolycorine 2, pancratistatin 3, its 7-deoxy analogue 4, and the unsaturated derivatives narciclasine 5 and deoxy analogue 6 have demonstrated a variety of antiviral activities (Figure 1). 5−13 The restricted availability of other natural lycorane-type alkaloids and the absence of a rapid synthetic route toward structural analogues has impeded further development of the antiviral pharmacophore.The development of synthetic strategies that allow rapid access to functionally dense, stereochemically defined cores not only enables the asymmetric synthesis of biologically active natural products, but opens synthetic entry to non-natural analogues. These analogues expand the structural diversity are natural products. Compounds 7−10 were accessed via total synthesis. Lycorine 1, pseudolycorine 2, pancratistatin 3, 7-deoxypancratistatin 4, narciclasine 5, 7-deoxynarciclasine 6, transdihydrolycoricidine 7, 3-epi-trans-dihydrolycoricidine 8, and 3-deoxytrans-dihydrolycoricidine 9.Letter pubs.acs.org/acsmedchemlett
Herein we have identified an optimal catalyst, Pd1Ag1.7, for the tandem reductive amination between nitroarenes and aldehydes (selectivity > 93%). Key to the success is the ability to control the compositions of the investigational Pd1-xAgx (x = 0-1) catalysts, as well as the clear composition dependent activity/selectivity trend observed in this study. This catalyst features a wide substrate scope, excellent recyclability, activity and selectivity under ambient conditions.
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