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| 4.76 | The title is: Structural Classification and Steroidal Characteristics of Guggulsterone: A Comprehensive Analysis of Its Chemical Architecture and Biological Implications |
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Title: Structural Classification and Steroidal Characteristics of Guggulsterone: A Comprehensive Analysis of Its Chemical Architecture and Biological Implications
Structural Elucidation and Absolute Configuration of Guggulsterones and Polypodane-Type Triterpenes from Guggul Resin
Guggulsterone is a plant steroid found in the resin of the guggul plant [1] and a phytosteroid derived from the oleo-gum resin of the critically endangered plant Commiphora wightii [2], containing two α,β-unsaturated carbonyls (enones) [3]. The bark of C. wightii hosts major steroidal metabolites, including E-guggulsterone (GS-E), Z-guggulsterone (GS-Z), GS-M, 4-pregnene-3,16-dione, guggulsterol-II, β-sitosterol, dehydroguggulsterone-M, guggulsterol-I, guggulsterol-VI, guggulsterol-III, and guggulsterol-IV [4]. GS-E and Z concentrations are higher in the bark than the stem across geographical regions, with total GS-E plus Z concentrations and hydro-alcoholic extract levels summarized below.
Guggulsterone (GS-E + GS-Z) Concentrations in C. wightii Tissues and Extracts
| Tissue/Extract Type | Concentration Range | Reference |
|---|---|---|
| Bark (total GS-E + Z) | 0.55 mg/g to 1.74 mg/g | [4] |
| Stem (total GS-E + Z) | 0.09 mg/g to 0.39 mg/g | [4] |
| Hydro-alcoholic bark extract (GS-E + Z) | 1.66 mg/g to 3.93 mg/g | [4] |
In addition to guggulsterones, guggul resin yields polypodane-type triterpenes. Myrrhanol A (1) and myrrhanone A (2) were isolated from the 50% aqueous methanolic extract of guggul resin via ethyl acetate partitioning, column chromatography, and HPLC [5][6]. Key structural details of these triterpenes are summarized below.
Structural Characteristics of Polypodane-Type Triterpenes Isolated from Guggul Resin
| Compound | Molecular Formula | IR Absorption Bands | Key NMR Features | Absolute Stereostructure | Reference |
|---|---|---|---|---|---|
| Myrrhanol A (1) | C₃₀H₅₂O₃ | 3432 cm⁻¹ (hydroxyl), 1670 cm⁻¹ (olefin) | Seven tertiary methyls; oxygen-bearing methine (3-H) and methylene (30-H₂); three trisubstituted olefins; quaternary oxygen-bearing carbon (C-8) | (3S,5R,8R,9R,10S)-3,8,30-trihydroxypolypoda-13E,17E,21E-triene (earlier 5S configuration [5]) | [5][6] |
| Myrrhanone A (2) | C₃₀H₅₀O₃ | 3453 cm⁻¹ (hydroxyl), 1709 cm⁻¹ (carbonyl), 1650 cm⁻¹ (olefin) | — | (5R,8R,9R,10S)-3-oxo-8,30-dihydroxypolypoda-13E,17E,21E-triene (confirmed by reduction to myrrhanol A [7]) | [5][6] |
Other polypodane-type triterpenes isolated from guggul resin include myrrhanol B (3), myrrhanone B (4), (8R)-3β,8-dihydroxypolypoda-13E,17E,21-triene (5), and (8R)-3-oxo-8-hydroxypolypoda-13E,17E,21-triene (6) [6].
Steroidal Architecture-Driven Molecular Interactions of Guggulsterone with Key Biological Targets
Guggulsterone, a steroid ketone isolated from the guggul tree (Commiphora mukul), exhibits diverse molecular interactions with key biological targets, underpinned by its steroidal architecture. Its molecular dynamics (MD) behavior when complexed with the SARS-CoV-2 ADP-ribose phosphatase (ARP) enzyme has been characterized via 100 ns simulations (Desmond tool, Schrodinger software), following stability validation in a 10 ns pre-simulation [8]. A suite of structural and dynamic metrics confirmed the stability of the guggulsterone-ARP complex, as summarized below:
Key Molecular Dynamic Metrics of Guggulsterone-SARS-CoV-2 ARP Complex (100 ns Simulation)
| Metric | Value Range/Mean |
|---|---|
| Macromolecular RMSD | 1–1.6 Å (constant, equilibrated) |
| Ligand RMSD | Well below 0.15–0.45 Å |
| Radius of gyration (rGyr) | 3.65–3.80 Å |
| Molecular surface area (MolSA) | 292–300 Ų (mean: 296 Ų) |
| Solvent-accessible surface area (SASA) | 40–120 Ų |
| Polar surface area (PSA) | 86–90 Ų |
| Total secondary structure element (SSE) preservation | 47.58% |
| Alpha-helices (SSE) | 28.58% |
| Beta-sheets (SSE) | 19.01% |
Critical residues including Ala38, Phe132, Leu160, Gly46, Gly47, Phe156, Asp157, and Ile131 interacted with guggulsterone via hydrogen bonds, hydrophobic interactions, or water-bridges, with over 5 amino acids consistently engaging the ligand during simulation [8].
Beyond viral target interactions, guggulsterone modulates several biological pathways and molecular targets. In pro-inflammatory signaling, it significantly reduced serum interleukin-6 (IL-6) compared to positive controls but had no significant effect on tumor necrosis factor-alpha (TNF-α) [9]. For the human glucocorticoid receptor agonist conformation (hGRag), it displayed a binding energy of -10.0 kcal/mol, placing it among dietary agents with high affinity for phosphatidylinositol 3-kinase alpha (PI3K-α) [10]. It also modulates the pregnane X receptor (PXR) as a dual agonist-antagonist, activating PXR while inhibiting rifampicin-induced PXR activation [11]. Additionally, guggulsterone inhibits P-glycoprotein (P-gp) in a concentration-dependent manner: it increases intracellular rhodamine-123 and daunorubicin levels in KB-C2 cells overexpressing P-gp (with no effect in non-expressing cells) and stimulates P-gp ATPase activity, suggesting it acts as a competitive inhibitor in the drug-binding domain [12].
Biotechnological Strategies for Enhanced Guggulsterone Production in Cell Cultures and Genomic Basis of Phytosterol Biosynthesis
Biotechnological strategies for enhanced guggulsterone production in cell cultures include clonal propagation, somatic embryogenesis, and cell suspension cultures, with additional optimizations via plant growth retardants and two-stage fed-batch systems. Genomic studies have also identified key genes and transcription factors involved in phytosterol biosynthesis in Commiphora weightii.
Biotechnological Strategies for Guggulsterone Production and Plant Regeneration
| Strategy | Medium/Additives | Key Outcome | Citation |
|---|---|---|---|
| Clonal propagation | MS medium + benzyladenine, kinetin, glutamine, thiamine HCl, activated charcoal | 60% survival at hardening stage; vigorous, uniform growth | [13] |
| Somatic embryogenesis | B5 medium + 2,4,5-trichlorophenoxy acetic acid, kinetin | 25% conversion of cotyledonary embryos to plantlets; 95% garden soil survival | [13] |
| Cell suspension cultures | MS medium + 2,4-D, kinetin (leaf callus) | 0.32% guggulsterone in 25-day-old cultures | [13] |
| Cell suspension cultures | MS medium + 2,4-D, kinetin (stem explants) | 1.97% guggulsterone | [13] |
| Cell suspension cultures | MS medium + 2,4-D, kinetin (2-month-old callus) | 0.22% guggulsterone | [13] |
| Plant growth retardant (CCC) | 1.0 mg l⁻¹ added on day 5 of inoculation | Maximum guggulsterone content (123 μg l⁻¹) | [14] |
| Plant growth retardant (ALAR) | 2.5 mg l⁻¹ added on day 10 after inoculation | Maximum guggulsterone production (116 μg l⁻¹) | [14] |
| Two-stage fed-batch culture | Twice feeding sugars on days 7 and 10 | ~3.5-fold increase in total guggulsterone yield (353 μg l⁻¹); 10.8 g l⁻¹ dry cell mass | [14] |
Genomic exploration of phytosterol biosynthesis in C. weightii utilized de novo draft genome sequencing of the high-guggulsterone genotype IC471203 (20.37 mg g⁻¹ content), collected from Rajasthan, India as part of 53 guggul germplasms [15]. Key genes identified include: cycloartenol synthase 1 (CAS1, seq id: g234.t1), with 83% identity to Arabidopsis CAS1 (sp|P38605|CAS1_ARATH) [15]; squalene epoxidase (g116.t1), with 75% identity to Arabidopsis SQE2 (NC_003071.7: c9726384-9723615_SQE2_ARATH_GeneID=816814), which diverts pathway flux via squalene 2,3 epoxide [15]; and 3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 (HMGR, g892.t1), with 67.5% homology to Solanum lycopersicum HMGR (NC_015439.3:c46508678-46505935_HMGR_SOLLC_GeneID=543702) [15]. Additionally, transcription factors WRKY1 and MYC2, which regulate phytosterol biosynthesis genes, were identified as orthologs in C. weightii [15].
Quantitative Analytical Methods for Guggulsterone Isomers in Resins, Formulations, and Plant Tissues
Thin-layer chromatography (TLC) is a key technique for identifying guggulsterone (GS) isomers in plant samples, with standard E-GS and Z-GS showing Rf values of 0.43 and 0.48, respectively [16]. Detection of isomers via Rf values revealed E-GS was absent only in sample Mf-E, while Z-GS was present in all samples; positive E-GS samples had Rf values of 0.43–0.44, and Z-GS samples had Rf values of 0.48–0.52 [16]. Scan spectra and λmax values further validated isomer identification: most samples matched the standard E-GS λmax of 250 nm (249–250 nm) except sample A (213 nm), and most aligned with the standard Z-GS λmax of 250 nm (251–257 nm) except Mf-F (235 nm) [16]. Quantitative analysis of GS isomers relies on high-performance liquid chromatography (HPLC) or similar techniques with linear calibration curves, as summarized below.
HPLC Calibration Parameters for Guggulsterone Isomers
| Study Citation | Isomer | Linear Range | Correlation Coefficient (r²) | Residual Standard Deviation | Limit of Detection (LOD) | Limit of Quantification (LOQ) |
|---|---|---|---|---|---|---|
| [16] | E-GS | 50–200 ng | 0.9979 | 3.142 | — | — |
| [16] | Z-GS | 50–200 ng | 0.9991 | 2.1873 | — | — |
| [17] | E-GS | 2–65 mg/mL | 0.99988 | — | 1.284 ng/μL | 3.890 ng/μL |
| [17] | Z-GS | 2–65 mg/mL | 0.99985 | — | 1.395 ng/μL | 4.227 ng/μL |
Quantification across matrices shows variable GS isomer distribution. In plant samples, bark had higher total GS concentrations (0.55–1.74 mg/g) than stems (0.09–0.39 mg/g) across regions, with hydro-alcoholic bark extracts containing 1.66–3.93 mg/g total GS [4]. Resin samples contained 0.122–3.022% (w/w) total GS [17]. Formulations exhibited region-specific differences: Indian tablets had 0.362% (w/w) total GS (0.116% E-GS, 0.246% Z-GS), Pakistani tablets had 0.130% (w/w) total GS (0.044% E-GS, 0.086% Z-GS), and USA tablets contained 2.944% (w/w) total GS (1.584% E-GS, 1.360% Z-GS) against a 2.5% label claim [17]. Individual plant samples displayed diverse isomer profiles, as detailed below.
GS Isomer Concentrations in Individual Plant Samples
| Sample ID | E-GS Concentration (% w/w) | Z-GS Concentration (% w/w) |
|---|---|---|
| Mf-A | — | 0.590 ± 0.0205 |
| Mf-E | — | 0.723 ± 0.0177 |
| Mf-F | 0.926 ± 0.0168 | — |
| Mf-B | 0.382 ± 0.0025 | 0.573 ± 0.0028 |
| Mf-C | 0.230 ± 0.0040 | 0.537 ± 0.0026 |
| Mf-D | 0.240 ± 0.0206 | 0.245 ± 0.0034 |
Note: All data in the table above is cited from [16].
Anti-Inflammatory, Anticancer, and Cytoprotective Biological Activities of Guggulsterone
Guggulsterone is a steroid ketone phytosteroid [12] derived from the oleo-gum resin of Commiphora mukul [11][18] and Commiphora wightii [2][19], with its bioactive E and Z isomers primarily mediating effects on lipid and cholesterol levels [19]. It is used to treat hyperlipidemia, obesity, arthritis, and inflammation [11], and functions as both an agonist and antagonist of the human pregnane X receptor (PXR) [11]. By antagonizing nuclear hormone receptors and decreasing cholesterol levels, guggulsterone contributes to the hypolipidemic effects of guggulu extracts [20]; guggulipid (Z-guggulsterone) specifically lowers serum LDL cholesterol and triglyceride levels, supporting cardiovascular benefits [20]. Guggulu preparations also contain volatile constituents including the ketone steroids Z- and E-guggulsterone [20], and chemists have developed synthetic routes from various steroid precursors to modify its structure for improved biological properties [2].
Guggulsterone and Guggulipid Biological Activities Across Models
| Activity Category | Intervention/Model | Key Findings | Citations |
|---|---|---|---|
| Anti-inflammatory | Cotton pellet-induced granuloma | Inhibition order: boswellic acid > withaferin A > guggulsterone; reduced serum IL-6 (no effect on TNF-α) | [9] |
| Anti-inflammatory | Mouse colitis models | Targeted lamina propria T cells to exhibit anti-inflammatory activity | [18] |
| Neuroprotective | Forced swim/tail suspension tests (neuroinflammation) | Attenuated behavioral abnormalities; prevented scopolamine-induced memory impairment via CREB-BDNF activation | [20] |
| Neuroprotective | Streptozotocin-induced dementia model | Beneficial effects via cholesterol-lowering, antioxidant, and antiacetylcholine esterase activities | [20] |
| Anti-inflammatory | GLNG-3 (guggul lipid-loaded formulation) | Maximum edema inhibition (99.83%), outperforming control (CEG, 50.54%) and indomethacin (79.25%) | [21] |
| Anticancer | HT-29 cells | Increased apoptosis via caspase-3/-8 activation; altered cIAP-1, cIAP-2, Bcl-2, truncated Bid, Fas, p-c-Jun, and p-JNK levels | [18] |
| Anticancer | HT-29 xenograft tumors (mice) | Reduced tumor size in treated mice | [18] |
| Anticancer | KB-C2 cells (P-gp overexpressing) | Increased intracellular rhodamine-123/daunorubicin (concentration-dependent); no effect in non-P-gp cells (P-gp inhibition) | [12] |
| Anticancer | P-gp ATPase activity assay | Stimulated activity, indicating P-gp substrate/competitive inhibitor role | [12] |
| Cytoprotective | H9C2 cells (doxorubicin-induced damage) | Reduced ROS (DHE staining, DCFH oxidation, lipid peroxidation); reversed apoptotic protein changes (PARP, caspase-3, bcl-2, bax, cytochrome C) | [22] |
| Cytoprotective | H9C2 cells (doxorubicin-induced damage) | Inhibited caspase-3 activity; reduced DNA condensation/chromatin fragmentation (Hoechst 33258 staining) | [22] |
| Molecular Interaction | Active site binding | Interacted with amino acid ASP 256 | [9] |
Structurally, guggulsterone is a steroid ketone [12], and its molecular interactions include binding to the active site amino acid ASP 256 [9]. These diverse activities—spanning anti-inflammatory, neuroprotective, anticancer, and cytoprotective effects—highlight guggulsterone’s potential as a multi-target therapeutic agent, with ongoing synthetic efforts aimed at enhancing its biological properties [2].
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