Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

Gao, Run-Duo; Tallon, Carolyn; Feinberg, Andrew P.; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1021/acsmedchemlett.2c00404

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…Primary hippocampal neurons were isolated from day-18 embryos of Sprague–Dawley rats acquired from Jackson Laboratories (Bar Harbor, ME), as previously described [ 30 – 32 ]. Briefly, the hippocampal tissue was dissected, gently titurated with trypsinization in calcium-free Hank’s balanced salt solution (HBSS, free of calcium, magnesium, and phenol red; Corning Inc., Manassass, VA) and cells were resuspended in Neurobasal media (Gibco, Waltham, MA) supplemented with B27 (Gibco), 1% antibiotic/antimitotic solution (Gibco), 10% FBS (Sigma, St. Louis, MO), HEPES (4.8 mM, Sigma) and L -glutamine (1.2 mM, Sigma).…”

Section: Methodsmentioning

confidence: 99%

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Tallon,

Bell,

Malvankar

et al. 2023

Transl Neurodegener

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Background Cognitive decline in Alzheimer’s disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity. Methods To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma. Results Similar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side. Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice.

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Section: Methodsmentioning

confidence: 99%

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Tallon,

Bell,

Malvankar

et al. 2023

Transl Neurodegener

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Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer’s disease

Tallon

Bell

Malvankar

et al. 2023

Preprint

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Background Cognitive decline in Alzheimer’s disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity.Methods To determine the therapeutic benefit of inhibiting this elevation, we evaluated the efficacy of PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. Changes in brain ceramide and sphingomyelin levels, Tau content, histopathology, and nSMase2 target engagement were monitored, as well as changes in the number of brain-derived EVs in plasma and their Tau content. Additionally, we evaluated the ability of PDDC to impede tau propagation in a murine model where an adeno-associated virus(AAV) encoding for P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus and the contralateral transfer to the dentate gyrus was monitored.Results Similar to human AD, PS19 mice exhibited increased brain ceramides and nSMase2 activity; both were completely normalized by PDDC treatment. PS19 mice exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all pathologic features of human AD. PDDC treatment significantly attenuated these aberrant changes. Mouse plasma isolated from PDDC-treated PS19 mice exhibited reduced levels of neuron- and microglia-derived EVs, the former carrying lower phosphorylated Tau(pTau) levels, compared to untreated mice. In the AAV tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly decreased tau spreading to the contralateral side.Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity leading to the slowing of tau spread in AD mice.

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Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry

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2024

Molecules

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Diesters of geminal diols (R-CH(O-CO-R′)2, RR′C(OCOR″)2, etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related “non-classical acylals”, as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

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Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

Cited by 3 publications

References 16 publications

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer’s disease

Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry

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