Chemistry, Biosynthesis and Pharmacology of Sarsasapogenin: A Potential Natural Steroid Molecule for New Drug Design, Development and Therapy

Abstract

Sarsasapogenin is a natural steroidal sapogenin molecule obtained mainly from Anemarrhena asphodeloides Bunge. Among the various phytosteroids present, sarsasapogenin has emerged as a promising molecule due to the fact of its diverse pharmacological activities. In this review, the chemistry, biosynthesis and pharmacological potentials of sarsasapogenin are summarised. Between 1996 and the present, the relevant literature regarding sarsasapogenin was obtained from scientific databases including PubMed, ScienceDirect, Scopus, and Google Scholar. Overall, sarsasapogenin is a potent molecule with anti-inflammatory, anticancer, antidiabetic, anti-osteoclastogenic and neuroprotective activities. It is also a potential molecule in the treatment for precocious puberty. This review also discusses the metabolism, pharmacokinetics and possible structural modifications as well as obstacles and opportunities for sarsasapogenin to become a drug molecule in the near future. More comprehensive preclinical studies, clinical trials, drug delivery, formulations of effective doses in pharmacokinetics studies, evaluation of adverse effects and potential synergistic effects with other drugs need to be thoroughly investigated to make sarsasapogenin a potential molecule for future drug development.

Keywords: biosynthesis; drug development; pharmacology; phytochemistry; sarsasapogenin; steroid.

Figure 1

Chemical structure of sarsasapogenin. Each carbon atom’s numbering system is displayed in the structure. A hydroxyl group is attached at the C3 position (in purple). At the other end of the rings C-25, a chiral atom is bound to a methyl group (C-27) in the S-configuration (in red).

Figure 2

Biosynthesis of sarsasapogenin.

Figure 3

Sarsasapogenin’s anti-inflammatory action in adipose tissue. While lean adipose tissue contributes to metabolic balance, inflammation regulation and insulin resistance, as obesity progresses, adipocytes enlarge and release adipokines, resulting in an increase in the production of pro-inflammatory factors and immune cell infiltration. Sarsasapogenin has been shown to inhibit pro-inflammatory cytokines, such as TNF-α, IL–1β, IL–6, IL-10, IL-12 and MCP-1, in white adipose tissue. TNF-α, tumour necrosis factor alpha; interleukin-1 beta, -6, -10 and -12; MCP-1, monocyte chemoattractant protein-1.

Figure 4

Mechanism of inhibition exhibited by sarsasapogenin in ear oedema. Sarsasapogenin reduced iNOS expression and PGE2 levels, which suppressed the inflammation generated by LPS and ameliorated ear oedema. MAPK, mitogen-activated protein kinase; ERK, extracellular-signal-regulated kinase; JNK, c-Jun N-terminal kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cell; P13K, phosphatidylinositol-3-kinase; Akt, Ak strain transforming; mTOR, mammalian target of rapamycin; TLR, Toll-like receptor.

Figure 5

Neuroprotection effect of sarsasapogenin. Sarsasapogenin may suppress the expression of pro-inflammatory M1 markers while elevating the expression of anti-inflammatory M2 biomarkers when taken orally. M2 promotes to the additional inhibition of the M1 marker, hence, assisting in the protection of neuroglial cells. IFN-γ, interferon gamma; iNOS, nitric oxide synthase; ROS, reactive oxygen species; Arg-1, arginase 1; TGF-β, transforming growth factor beta.

Figure 6

Sarsasapogenin mechanism of action in inflammasome activation and AGE. NLRP3 is triggered by a wide variety of stimuli, including LPS via Toll-like receptors (TLR), which results in the manufacture of the cytokine precursor via NF-kB and other inflammasome constituents, including NLRP3. Sarsasapogenin inhibits the activation of the NLRP3 inflammasome and the AGE pathway, vastly improving diabetic nephropathy in rats. Abbreviations: N-GSDMD, N-terminal Gasdermin-D; GSDMD, Gasdermin-D; NLRP3, NLR family pyrin domain containing 3; NLRC4, NLR Family CARD Domain Containing 4; AGE, Advanced glycation end products; PKC, Protein kinase C.

Figure 7

Chemical structures of sarsasapogenin-derived compounds (2a–2e and 3a–3e).

Figure 8

Sarsasapogenin-derived compounds isolated and identified from Asparagus adscendens and Asparagus racemosus.

Figure 9

Chemical structures of isosarsasapogenin and other sarsasapogenin-derived compounds (5a–5c and 6a–6d).

Figure 10

Schematic representation of the drug delivery strategy for sarsasapogenin-loaded liposomes augmented with a targeting moiety, such as cell-penetrating peptides (CPPs), to enhance localisation and bioavailability of the bioactive molecule.