Chemistry, Pharmacology and Therapeutic Potential of Swertiamarin – A Promising Natural Lead for New Drug Discovery and Development

Abstract

Swertiamarin, a seco-iridoid glycoside, is mainly found in Enicostemma littorale Blume (E. littorale) and exhibits therapeutic activities for various diseases. The present study aimed to provide a review of swertiamarin in terms of its phytochemistry, physicochemical properties, biosynthesis, pharmacology and therapeutic potential. Relevant literature was collected from several scientific databases, including PubMed, ScienceDirect, Scopus and Google Scholar, between 1990 and the present. This review included the distribution of swertiamarin in medicinal plants and its isolation, characterization, physicochemical properties and possible biosynthetic pathways. A comprehensive summary of the pharmacological activities, therapeutic potential and metabolic pathways of swertiamarin was also included after careful screening and tabulation. Based on the reported evidence, swertiamarin meets all five of Lipinski’s rules for drug-like properties. Thereafter, the physicochemical properties of swertiamarin were detailed and analyzed. A simple and rapid method for isolating swertiamarin from E. littorale has been described. The present review proposed that swertiamarin may be biosynthesized by the mevalonate or nonmevalonate pathways, followed by the seco-iridoid pathway. It has also been found that swertiamarin is a potent compound with diverse pharmacological activities, including hepatoprotective, analgesic, anti-inflammatory, antiarthritis, antidiabetic, antioxidant, neuroprotective and gastroprotective activities. The anticancer activity of swertiamarin against different cancer cell lines has been recently reported. The underlying mechanisms of all these pharmacological effects are diverse and seem to involve the regulation of different molecular targets, including growth factors, inflammatory cytokines, protein kinases, apoptosis-related proteins, receptors and enzymes. Swertiamarin also modulates the activity of several transcription factors, and their signaling pathways in various pathological conditions are also discussed. Moreover, we have highlighted the toxicity profile, pharmacokinetics and possible structural modifications of swertiamarin. The pharmacological activities and therapeutic potential of swertiamarin have been extensively investigated. However, more advanced studies are required including clinical trials and studies on the bioavailability, permeability and administration of safe doses to offer swertiamarin as a novel candidate for future drug development.

Keywords:

• swertiamarin
• Enicostemma littorale
• biosynthesis
• metabolic pathway
• molecular targets
• inflammatory cytokines

Acknowledgments

The authors thank Universiti Kuala Lumpur Royal College of Medicine Perak, Malaysia, for providing necessary facilities and resources to complete this study for publication.

Highlights

• Swertiamarin is a seco-iridoid glycoside that exhibits a broad spectrum of pharmacological properties.

• It meets Lipinski’s rule of five for drug-likeness properties.

• It is biosynthesized by mevalonate or nonmevalonate pathways followed by the seco-iridoid pathway.

• This review emphasizes the distribution, isolation, characterization, physicochemical properties, biosynthetic pathways, toxicity profiles, biological properties, metabolic pathways, pharmacokinetics and structural modifications of swertiamarin.

• This review accelerates the development and utilization of swertiamarin as a promising natural lead for new drug discovery in the near future.

Abbreviations

10-HGO, 10-hydroxygeraniol oxidoreductase; 5-HT, 5-hydroxytryptamine; 7DLS, 7-deoxyloganetic acid synthase; AACT, Acetoacetyl-CoA thiolase; Akt, Serine/threonine protein kinase; ALT, Alanine aminotransferase; AMPK, Adenosine monophosphate-activated protein kinase; AST, Aspartate transaminase; AT1R, Angiotensin II type 1 receptor; BH₃, Trihydridoboron; CCl₄, Carbon tetrachloride; CGBVS, Chemical genomics-based virtual screening; CMK, 4-diphosphocytidyl-2-Cmethyl-D-erythritol kinase; CMS, 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase; Con A, Concanavalin A; CYP, Cytochrome; DAST, Diethylaminosulphurtrifluoride; d-GaIN, Galactosamine; DLGT, 7-deoxyloganetic acid glucosyltransferase; DL7H, 7-deoxyloganic acid 7-hydroxylase; LAMT, Loganic acid O-methyltransferase; SLS, Secologanin synthase; DMAPP, dimethylallyl diphosphate; DMF, Dimethylformamide; DMN, Dimethylnitrosamine; DXR, 1-deoxy-D-xylulose-5-phosphate reductoisomerase; DXS, 1-deoxy-D-xylulose-5-phosphate synthase; ERK, Extracellular signal-regulated kinase; ESI-MS, Electrospray ionization mass spectrometry; FAS, Fatty acid synthase; FLS, Fibroblast-like synoviocytes; FTIR, Fourier-transform Infrared spectroscopy; G10H, Geraniol 10-hydroxylase; GLUT-4, Glucose transporter type 4; H₂O₂, Hydrogen peroxide; HA, Hemagglutinating antibody; HbA1c, Hemoglobin A1c; HDL, High-density lipoprotein; HDR, 1-hydroxy-2-methyl-2-butenyl 4-diphosphate reductase; HDS, 1-hydroxy-2-methyl-2-butenyl 4-diphosphate synthase; HepG2, Human liver cancer cell line; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; HMGR, Hydroxymethyglutaryl-CoA reductase; HMGS, Hydroxymethyglutaryl-CoA synthase; HSC, Hepatic stellate cells; i.p., intraperitoneal; IC₅₀, Half maximal inhibitory concentration; IDI, Isopentenyl diphosphate isomerase; IL, Interleukin; iNOS, Inducible nitric oxide synthase; IRS, Iridoid synthase; LDL, Low-density lipoprotein; LPS, Lipopolysaccharide; MAPK, Mitogen-activated protein kinase; MCAO, Multi-conjugate adaptive optics; mCPBA, m-chloroperbenzoic acid; MDA, Malondialdehyde; MECS, 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase; MMT, Manual muscle testing; mRNA, Messenger RNA; MVD, Mevalonate 5-diphosphate decarboxylase; MVK, Mevalonate kinase; NAFLD, Nonalcoholic fatty liver disease; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NMR, Nuclear magnetic resonance spectroscopy; NQO1, NAD(P)H, quinone oxidoreductase-1; Nrf2, Nuclear factor E2-related factor 2; P.O., Oral administration; PI3K, Phosphatidylinositol 3-kinase; PMK, Mevalonate 5-phosphate kinase; PPAR-α, Peroxisome proliferator-activated receptor alpha; PTZ, Pentylenetetrazole; RANKL, Osteoclastogenic mediator; RAS, Renin-angiotensin system; s.c., Subcutaneous; SAR, Structure activity relationship; SRB, Sulfate reducing bacteria; SREBP-1, Sterol-regulatory element-binding protein-1; STZ, Streptozotocin; TG, Triglyceride; TGF-β1, Transforming growth factor-β1; THF, Tetrahydrofuran; TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labelling; UV, Ultraviolet; XO, xanthine oxidase.

Consent for Publication

The final version of the manuscript was reviewed by all the authors and consented to its submission.

Author Contributions

N.S.M.F., and M.S. conceived the idea, designed, collected the literature, interpreted the data, analyzed the data, drafted and revised the manuscript. All the authors have made noteworthy contributions to the study design, data collection, review and interpretation; have engaged in the drafting or revision of the article; have agreed to submit to the current journal; have given final approval of the version to be published; and have agreed to be responsible for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

There is no funding to report.