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Anti-aging and anti-inflammatory prodrugs and methods of use thereof

A technology for senescent cells and inflammatory diseases, which is used in anti-inflammatory agents, pharmaceutical formulations, anti-toxic agents, etc.

Pending Publication Date: 2022-04-12
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, specific and efficient clearance of multiple senescent cell types remains challenging due to their complexity and heterogeneity (Kirkland, et al. J AmGeriatr Soc 65, 2297-2301 (2017); Lozano-Torres et al. , Nature Reviews Chemistry 3, 426-441(2019))

Method used

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  • Anti-aging and anti-inflammatory prodrugs and methods of use thereof
  • Anti-aging and anti-inflammatory prodrugs and methods of use thereof
  • Anti-aging and anti-inflammatory prodrugs and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0314] Materials and methods

[0315] Synthesis of SSK1 and SSK2

[0316] All reactions were performed under an atmosphere of nitrogen with dry solvents under anhydrous conditions unless otherwise stated. Reagents were purchased at the highest commercial quality without further purification unless otherwise stated. Yields are measured by chromatography.

[0317] The reaction was monitored by thin layer chromatography on a plate (GF254) supplied by Yantai Chemicals (China) using UV light as the developer, ethanol solutions of phosphomolybdic acid and cerium sulfate and heat as the developer. Unless otherwise specified, silica gel (200-300 mesh) provided by Tsingtao Haiyang Chemicals (China) was used for flash column chromatography.

[0318] In the Brüker Advance 600 ( 13 C 150MHz, 19 F 565MHz) and Brüker Advance 400 ( 1 (400 MHz) NMR spectra were recorded on a spectrometer using residual undeuterated solvent (at 3.31 ppm 1 CD at H NMR 3 OD, 49.0ppm 13C NMR) calibration...

Embodiment 2

[0419] Effective management of rhesus macaques infected with SARS-CoV-2 by reducing inflammation

[0420] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic. The transition from mild to severe life-threatening during SARS-CoV-2 infection can be rapid (Huang et al., 2020; Wang et al., 2020). Approximately 15% of patients develop severe pneumonia, leading to respiratory failure and high in-hospital mortality, especially in elderly patients (Grasselli et al., 2020; Yang et al., 2020). Therefore, this situation leads to an urgent need for effective COVID-19 therapeutic strategies. Recently, it was reported that the FDA-approved antiviral drug remdesivir can shorten the recovery time of COVID-19 in patients with mild symptoms. However, it has shown limitations in treating severe or critically ill patients (Grein et al., 2020; Wang et al., 2020). In this regard, there is still an urgent need to develop effectiv...

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Abstract

Provided are anti-aging and anti-inflammatory prodrugs designed from cytotoxic agents incorporated into sites that can be cleaved by SA-beta-gal after delivery of the prodrug in vivo by chemically modifying the cytotoxic agents to release the active parent drug. The prodrugs include a galactosyl moiety, a benzyloxycarboxyl moiety, and a cytotoxic agent moiety, which are preferably acetylated. An anti-aging prodrug for selectively killing one or more senescent cells and / or reducing acute or chronic inflammatory responses in a subject in need thereof is administered to the subject in a therapeutically effective amount of the anti-aging prodrug. The disclosed compositions are useful for reducing one or more symptoms associated with an aging-related disease or disorder or an inflammatory disorder, such as virus-mediated inflammation, in a subject.

Description

[0001] field of invention [0002] The present invention relates to compounds capable of selectively killing senescent cells over non-senescent cells, ie, anti-aging compounds, and methods of use thereof. [0003] Background of the invention [0004] Aging is a major risk factor for physiological degeneration, increased chronic morbidity, and age-specific mortality (Lopez-Otin, et al., Cell 153, 1194-1217 (2013)). During aging, senescent cells accumulate in multiple tissues and lead to tissue dysfunction (van Deursen, et al., Nature 509, 439-446 (2014); McHugh, et al., J CellBiol 217, 65-77 (2018)). Senescent cells also secrete a variety of proinflammatory factors, termed the senescence-associated secretory phenotype (SASP), which contribute to age-related physical decline (Coppe, et al., PLoS Biol 6, 2853-2868 (2008); Coppe, et al. People, Annu Rev Pathol 5, 99-118 (2010)). Eliminating senescent cells has emerged as an attractive potential approach to ameliorate age-related ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073A61K31/7068A61P39/00A61P29/00
CPCA61K31/7068A61P29/00A61K47/549
Inventor 邓宏魁罗佗平蔡雨生周欢欢朱银华赵晶晶董杰斌郦宏刚
Owner PEKING UNIV
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