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J Steroid Biochem Mol Biol. 2014 Sep;143:323-33. doi: 10.1016/j.jsbmb.2014.04.006. Epub 2014 May 9.

Synthesis of diosgenin analogues as potential anti-inflammatory agents.

Author information

1
Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
2
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India; Department of Chemistry, University of Ilorin, Ilorin, Nigeria.
3
Molecular and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
4
Organic Chemistry Unit, Department of Chemistry, University of Ibadan, Ibadan, Nigeria.
5
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India. Electronic address: as.negi@cimap.res.in.
6
Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India. Electronic address: du.bawankule@cimap.res.in.

Abstract

We herein report the synthesis of diosgenin analogues from commercially available diosgenin as the starting material. The structures of newly synthesised compounds were confirmed by (1)H NMR, (13)C NMR and mass spectrometry. All analogues were evaluated for in-vitro anti-inflammatory profile against LPS-induced inflammation in primary peritoneal macrophages isolated from mice by quantification of pro-inflammatory (TNF-α, IL-6 and IL-1β) cytokines in cell culture supernatant using the ELISA technique followed by in-vitro cytotoxicity study. Among the synthesised analogues, analogue 15 [(E) 26-(3',4',5'-trimethoxybenzylidene)-furost-5en-3β-acetate)] showed significant anti-inflammatory activity by inhibiting LPS-induced pro-inflammatory cytokines in a dose-dependent manner without any cytotoxicity. Efficacy and safety of analogue 15 were further validated in an in-vivo system using LPS-induced sepsis model and acute oral toxicity in mice. Oral administration of analogue 15 inhibited the pro-inflammatory cytokines in serum, attenuated the liver and lung injury and reduced the mortality rate in sepsis mice. Acute oral toxicity study showed that analogue 15 is non-toxic at higher dose in BALB/c mice. Molecular docking study revealed the strong binding affinity of diosgenin analogues to the active site of the pro-inflammatory proteins. These findings suggested that analogue 15 may be a useful therapeutic candidate for the treatment of inflammatory diseases.

KEYWORDS:

Diosgenin; Docking; Inflammation; Lipopolysaccharide; Macrophage; Mice; Sepsis

PMID:
24816230
DOI:
10.1016/j.jsbmb.2014.04.006
[Indexed for MEDLINE]
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