Trichoplusia ni Transcriptomic Responses to the Phytosaponin Aglycone Hederagenin: Sex-Related Differences.

Many plant species, particularly legumes, protect themselves with saponins. Previously, a correlation was observed between levels of oleanolic acid-derived saponins, such as hederagenin-derived compounds, in the legume Medicago truncatula and caterpillar deterrence. Using concentrations that reflect the foliar levels of hederagenin-type saponins, the sapogenin hederagenin was not toxic to 4th instar caterpillars of the cabbage looper Trichoplusia ni nor did it act as a feeding deterrent. Female caterpillars consumed more diet than males, presumably to obtain the additional nutrients required for oogenesis, and are, thus, exposed to higher hederagenin levels. When fed the hederagenin diet, male caterpillars expressed genes encoding trypsin-like proteins (LOC113500509, LOC113501951, LOC113501953, LOC113501966, LOC113501965, LOC113499659, LOC113501950, LOC113501948, LOC113501957, LOC113501962, LOC113497819, LOC113501946, LOC113503910) as well as stress-responsive (LOC113503484, LOC113505107) proteins and cytochrome P450 6B2-like (LOC113493761) at higher levels than females. In comparison, female caterpillars expressed higher levels of cytochrome P450 6B7-like (LOC113492289). Bioinformatic tools predict that cytochrome P450s could catalyze the oxygenation of hederagenin which would increase the hydrophilicity of the compound. Expression of a Major Facilitator Subfamily (MFS) transporter (LOC113492899) showed a hederagenin dose-dependent increase in gene expression suggesting that this transporter may be involved in sapogenin efflux. These sex-related differences in feeding and detoxification should be taken into consideration in insecticide evaluations to minimize pesticide resistance.

Late-Stage Derivatization of Oleanolic Acid-Based Anti-HIV-1 Compounds.

A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the ß-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.

An asiatic acid derived trisulfamate acts as a nanomolar inhibitor of human carbonic anhydrase VA.

This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1-5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21-25. Inhibition assays against hCAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23, exhibited a Ki value of 88.1 nM for hCA VA, and a derivative of asiatic acid, compound 25, displayed an even lower Ki value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against hCA VA when compared to the benchmark compound acetazolamide (AAZ), which had a Ki value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse hCA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective hCA VA inhibitor prompts further exploration of its therapeutic applications.

Astraoleanosides E-P, oleanane-type triterpenoid saponins from the aerial parts of Astragalus membranaceus Bunge and their ß-glucuronidase inhibitory activity.

Historically, Astragalus membranaceus Bunge has been used as a beneficial medicinal plant, particularly in the Asian traditional medical systems, for the treatment of various human diseases such as stomach ulcers, diarrhea, and respiratory issues associated with phlegm. In this study, a phytochemical characterization of the aerial parts of A. membranaceusled to the isolation of 29 oleanane-type triterpenoid saponins, including 11 new compounds named astraoleanosides E-P (6-9, 13, 14, 18-22), as well as 18 known ones. The structures of these compounds were elucidated using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry. Among them, astraoleanoside H (9) and cloversaponin III (15) demonstrated the most potent ß-glucuronidase inhibitory activities, with IC50 values of 21.20 ± 0.75 and 9.05 ± 0.47 µM, respectively, compared to the positive control d-saccharic acid 1,4-lactone (IC50 = 20.62 ± 1.61 µM). Enzyme kinetics studies were then conducted to investigate the type of inhibition exhibited by these active compounds. In addition, the binding mechanism, key interactions, binding stability, and dynamic behavior of protein-ligand complexes were investigated through in silico approaches, such as molecular docking and molecular dynamics simulations. These findings highlight the promising potential of triterpenoid saponins from A. membranaceus as lead compounds for ß-glucuronidase inhibitors, offering new possibilities for the development of therapeutic agents targeting various diseases where ß-glucuronidase plays a crucial role.

Synthesis of methotrexate-betulonic acid hybrids and evaluation of their effect on artificial and Caco-2 cell membranes.

An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids with a (tert-butoxycarbonylamino)-3,6-dioxa-8-octanamine (Boc-DOOA) linkage has been developed. Reaction of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-betulonamide with methotrexate resulted in a mixture of isomeric conjugates which were separated by column chromatography. Their structures and composition have been fully established by 1H NMR, 13C spectra, FAB mass spectrometry and elemental analysis. The identity of conjugates was confirmed by LC-MS data. Membranotropic properties of the new hybrids were assessed on the basis of their interactions with artificial lipid membranes by differential scanning calorimetry (DSC) method. The ability of the conjugates to penetrate Caco-2 cells is inferior to methotrexate. Probably, this is due to the increasing lipophilicity, the affinity of these hybrid molecules for the lipid bilayer increases, which is confirmed by experiments with artificial membranes.

Integrative transcriptome and single-cell sequencing technology analysis of the potential therapeutic benefits of oleanolic acid in liver injury and liver cancer.

BACKGROUND: Oleanolic acid has important hepatoprotective effects and inhibits liver tissue carcinogenesis. The aim of this study was to investigate the mechanism of action of oleanolic acid in inhibiting liver injury and liver cancer. METHOD: In this study, we applied differential gene analysis and gene enrichment analysis to identify the targets of oleanolic acid for the treatment of liver injury. And this study also applied Cibersort and GSVA methods to investigate the targets of oleanolic acid in liver injury. Based on oleanolic acid targets, we explored the major targets and further explored the role of the major targets in liver cancer. This study used the oncoPredict and the TIDE algorithm to predict the effect of oleanolic acid on drug resistance. Finally, the binding effect of oleanolic acid to relevant targets was explored using molecular docking techniques. RESULT: In this study, oleanolic acid was found to inhibit liver injury and promote liver regeneration mainly by promoting elevated expression of HMOX1. Oleanolic acid can inhibit oxidative stress and promotes Ferroptosis in liver injury. In liver cancer, we identified that the main target of oleanolic acid is HMOX1 and HDAC1. And we determined that HMOX1 promotes Ferroptosis in liver cancer. This reduced the sensitivity of liver cancer to targeted therapies and immunotherapy. Molecular docking showed high binding of oleanolic acid to HDAC1 and HMOX1. CONCLUSIONS: Oleanolic acid is an antioxidant by promoting high expression of HMOX1 and promotes the development of Ferroptosis in liver cancer and liver injury.

Oleanolic Acid Complexation with Cyclodextrins Improves Its Cell Bio-Availability and Biological Activities for Cell Migration.

Wound healing is a complex process to restore skin. Plant-derived bioactive compounds might be a source of substances for the treatment of wounds stalled in a non-resolving stage of wound healing. Oleanolic acid (OA), a pentacyclic triterpene, has shown favorable wound healing properties both in vitro and in vivo. Unfortunately, OA cannot be solubilized in aqueous media, and it needs to be helped by the use of dimethyl sulfoxide (DMSO). In this paper, we have shown that cyclodextrins (CDs) are a good alternative to DMSO as agents to deliver OA to cells, providing better features than DMSO. Cyclodextrins are natural macromolecules that show a unique tridimensional structure that can encapsulate a wide variety of hydrophobic compounds. We have studied the cyclodextrin-encapsulated form of OA with OA/DMSO, comparing their stability, biological properties for cell migration, and cell viability. In addition, detailed parameters related to cell migration and cytoskeletal reorganization have been measured and compared. Our results show that OA-encapsulateds compound exhibit several advantages when compared to non-encapsulated OA in terms of chemical stability, migration enhancement, and preservation of cell viability.

Foegraecumoside O and P, a Pair of Triterpenoid Saponins with a 4/5/6 Fused Tricyclic Oleanane Carbon Skeleton from Lysimachia foenum-graecum Hance.

Lysimachia foenum-graecum Hance (Primulaceae) is a medicinal plant used for cold, pain, ascariasis, etc., in China. Triterpenoid saponins have been found to be the main components of this genus. In this work, a pair of oleanane-type triterpenoid saponins with an unprecedented 4/5/6 fused tricyclic skeleton, foegraecumoside O (1) and foegraecumoside P (2) were isolated from the butanol fraction of the aerial parts of L. foenum-graecum. Their structures were determined using chemical methods and extensive spectroscopic analyses, along with quantum chemical calculations. Compound 2 displayed moderate cytotoxicity against HepG2, MGC-803, T24, NCI-H460, A549, and A549/CDDP (drug-resistant lung-cancer cell line) with IC50 at 12.4-19.2 µM in an MTT assay, comparing with the positive control doxorubicin, which had IC50 at 0.53-4.92 µM, but was inactive for A549/CDDP. Furthermore, a possible biosynthetic pathway for forming compounds 1 and 2 was proposed.

Comparative genomics of the medicinal plants Lonicera macranthoides and L. japonica provides insight into genus genome evolution and hederagenin-based saponin biosynthesis.

Lonicera macranthoides (LM) and L. japonica (LJ) are medicinal plants widely used in treating viral diseases, such as COVID-19. Although the two species are morphologically similar, their secondary metabolite profiles are significantly different. Here, metabolomics analysis showed that LM contained ~86.01 mg/g hederagenin-based saponins, 2000-fold higher than LJ. To gain molecular insights into its secondary metabolite production, a chromosome-level genome of LM was constructed, comprising 9 pseudo-chromosomes with 40 097 protein-encoding genes. Genome evolution analysis showed that LM and LJ were diverged 1.30-2.27 million years ago (MYA). The two plant species experienced a common whole-genome duplication event that occurred ∼53.9-55.2 MYA before speciation. Genes involved in hederagenin-based saponin biosynthesis were arranged in clusters on the chromosomes of LM and they were more highly expressed in LM than in LJ. Among them, oleanolic acid synthase (OAS) and UDP-glycosyltransferase 73 (UGT73) families were much more highly expressed in LM than in LJ. Specifically, LmOAS1 was identified to effectively catalyse the C-28 oxidation of ß-Amyrin to form oleanolic acid, the precursor of hederagenin-based saponin. LmUGT73P1 was identified to catalyse cauloside A to produce α-hederin. We further identified the key amino acid residues of LmOAS1 and LmUGT73P1 for their enzymatic activities. Additionally, comparing with collinear genes in LJ, LmOAS1 and LmUGT73P1 had an interesting phenomenon of 'neighbourhood replication' in LM genome. Collectively, the genomic resource and candidate genes reported here set the foundation to fully reveal the genome evolution of the Lonicera genus and hederagenin-based saponin biosynthetic pathway.

Nine-valent oleanolic acid conjugates as potent inhibitors blocking the entry of influenza A virus.

The influenza pandemic remains a major public health challenge that endangers the lives of many vulnerable and immune-compromised individuals worldwide. The high infectivity and genetic variability of influenza virus make it particularly challenging to design effective drugs to inhibit the virus. In previous studies, we determined that oleanolic acid (OA) and its derivatives block interactions between influenza and host cells, thus endowing OA with anti-viral efficacy. Inspired by the role of cluster glycosides in the interactions between hemagglutinins (HA) and sialic acid receptors (SA), we designed and synthesized a series of OA nonamers via the CuAAC reaction, and evaluated their anti-viral activities in vitro. We determined that among these nonamers, compound 15 displayed the highest potency (IC50 = 5.23 µM), equivalent to the antiviral drug oseltamivir which is routinely prescribed for influenza A virus strain A/WSN/33 (H1N1). In addition, these compounds also displayed antiviral activity against influenza B. Mechanistic experiments indicated that OA nonamers can effectively target the influenza HA protein. This study collectively demonstrates that multivalent structure-activity binding strategy is an effective method for designing influenza virus inhibitors.

Oleanolic Acid Glycosides from Scabiosa caucasica and Scabiosa ochroleuca: Structural Analysis and Cytotoxicity.

In the field of research on medicinal plants from the Armenian flora, the phytochemical study of two Scabiosa L. species, S. caucasica M. Bieb. and S. ochroleuca L. (Caprifoliaceae), has led to the isolation of five previously undescribed oleanolic acid glycosides from an aqueous-ethanolic extract of the roots: 3-O-α-L-rhamnopyranosyl-(1→3)-ß-D-glucopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→4)-ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl ester, 3-O-ß-D-xylopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-ß-D-glucopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→4)-ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl ester, 3-O-ß-D-xylopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-ß-D-glucopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→4)-ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid, 3-O-ß-D-xylopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-ß-D-xylopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→4)-ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl ester, 3-O-α-L-rhamnopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→4)-ß-D-glucopyranosyl-(1→4)-ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl ester. Their full structural elucidation required extensive 1D and 2D NMR experiments, as well as mass spectrometry analysis. For the biological activity of the bidesmosidic saponins and the monodesmosidic saponin, their cytotoxicity on a mouse colon cancer cell line (MC-38) was evaluated.

Comprehensive metabolic profiles of Achyranthes bidentate in rat serum via ultra-high performance liquid chromatography time-of-flight mass spectrometry and their correlation with osteoinductive activity.

The osteoinductive effect of crude and salt-processed Achyranthes bidentata is associated with the serum metabolites. Grey relationship analysis between the serum metabolites and osteoinductive effect will help to clarify the bioactive serum metabolites. First, an ultra-high performance liquid chromatography time-of-flight mass spectrometry method was used to develop serum metabolic fingerprint of rats after oral administration of crude and salt-processed Achyranthes bidentata. The MS1 and MS2 data of serum metabolites were scanned in the range of m/z 100-1500 and 50-1200, respectively. The chemical structures of the metabolites were thoroughly elucidated. Two prototypes and twelve metabolites have been identified. Second, osteoblasts were cultured with the drug-containing serum at different time points. The osteoinductive effect of crude and salt-processed Achyranthes bidentata was evaluated by detecting the proliferation rate and alkaline phosphatase activity of osteoblasts. Third, grey correlation analysis was utilized to elucidate the spectral-effect relationship between serum metabolic fingerprints and osteoinductive effect. Finally, the correlation coefficients of ten metabolites, i.e., oleanolic acid, poststerone-M1, chikusetsusaponin V-M1, oleanolic acid-M2, oleanolic acid-M4, spinacoside D-M1, chikusetsusaponin I-M1, betavulgaroside IV-M2, chikusetsusaponin IVa and achyranthoside IV-M1 were above 0.7. Collectively, our work will provide helpful knowledge for the future research on Achyranthes bidentata.

Five New Oleanane Triterpene Saponins from Camellia petelotii and Their Alpha-glucosidase Inhibitory Activity.

Five new triterpenoid glycosides, named campetelosides A-E (1-5), together with three known compounds, chikusetsusaponin IVa (6), umbellatoside B (7), and silvioside E (8) were isolated from the leaves of Camellia petelotii (Merr.) Sealy. Their chemical structures were determined by interpretations of HR-ESI-MS and NMR spectra. In addition, compounds 1-8 were evaluated for their α-glucosidase inhibitory effects. Compounds 1-3 significantly showed α-glucosidase inhibitory activity with IC50 values of 166.7±6.0, 45.9±2.6, and 395.3±10.5 µM, respectively, compared to that of the positive control, acarbose, with an IC50 value of 200.4±10.5 µM.

Saikosaponin A and Its Epimers Alleviate LPS-Induced Acute Lung Injury in Mice.

The purpose of this work was to illustrate the effect of processing with vinegar on saikosaponins of Bupleurum chinense DC. (BC) and the protective effects of saikosaponin A (SSA), saikosaponin b1 (SSb1), saikosaponin b2 (SSb2), and saikosaponin D (SSD) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice. We comprehensively evaluated the anti-inflammatory effects and potential mechanisms of SSA, SSb1, SSb2, and SSD through an LPS-induced ALI model using intratracheal injection. The results showed that SSA, SSb1, SSb2, and SSD significantly decreased pulmonary edema; reduced the levels of IL-6, TNF-α, and IL-1ß in serum and lung tissues; alleviated pulmonary pathological damage; and decreased the levels of the IL-6, TNF-α, and IL-1ß genes and the expression of NF-κB/TLR4-related proteins. Interestingly, they were similar in structure, but SSb2 had a better anti-inflammatory effect at the same dose, according to a principal component analysis. These findings indicated that it may not have been comprehensive to only use SSA and SSD as indicators to evaluate the quality of BC, especially as the contents of SSb1 and SSb2 in vinegar-processed BC were significantly increased.

Hedyocoronins A and B: two new oleanane saponins from the aerial parts of Hedyotis coronaria.

Two new oleanane saponins, hedyocoronin A (1) and hedyocoronin B (2), were isolated from the aerial parts of Hedyotis coronaria (Kurz) Craib, Rubiaceae, collected at Da Oai district, Lam Dong province in Vietnam. Their chemical structures were elucidated by HR-MS, 1D and 2D-NMR spectra, along with the comparison with those reported in the literature. Compounds 1 and 2 showed weak cytotoxicity against KB and HeLa-S3 cancer cell lines with IC50 values of more than 54 µM.

Discovery of 12ß-oxygenated oleanolic acid alkyl esters as potent and selective FXR modulators exhibiting hyperglycemia amelioration in vivo.

Farnesoid X receptor (FXR) ligands have been actively pursued to treat metabolic disorders, liver and bile diseases, among others. Starting from a widely occurring natural product, oleanolic acid (OA), we discovered potent and selective FXR modulator from the 12ß-oxygenated OA alkyl esters, with the assistance of molecular modeling. The representative compound 7b modulated some FXR downstream genes involved in glucose and lipid metabolism in cells, and significantly improved hyperglycemia in KKay fat mice fed with high fat diet, through the reduction of mRNA expression of gluconeogenesis genes PEPCK and G6Pase. This study provides a new series of selective FXR modulator, as well as the in vitro and in vivo evidence for their potential to improve hyperglycemia in diabetic mice through FXR antagonism.

Novel Triterpenic Acid-Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents.

Pentacyclic triterpenes, such as betulinic, ursolic, and oleanolic acids are efficient and selective anticancer agents whose underlying mechanisms of action have been widely investigated. The introduction of N-bearing heterocycles (e.g., triazoles) into the structures of natural compounds (particularly pentacyclic triterpenes) has yielded semisynthetic derivatives with increased antiproliferative potential as opposed to unmodified starting compounds. In this work, we report the synthesis and biological assessment of benzotriazole esters of betulinic acid (BA), oleanolic acid (OA), and ursolic acid (UA) (compounds 1-3). The esters were obtained in moderate yields (28-42%). All three compounds showed dose-dependent reductions in cell viability against A375 melanoma cells and no cytotoxic effects against healthy human keratinocytes. The morphology analysis of treated cells showed characteristic apoptotic changes consisting of nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption. rtPCR analysis reinforced the proapoptotic evidence, showing a reduction in anti-apoptotic Bcl-2 expression and upregulation of the pro-apoptotic Bax. High-resolution respirometry studies showed that all three compounds were able to significantly inhibit mitochondrial function. Molecular docking showed that compounds 1-3 showed an increase in binding affinity against Bcl-2 as opposed to BA, OA, and UA and similar binding patterns compared to known Bcl-2 inhibitors.

Insights into isostructural and non-isostructural crystals of esters of oleanolic acid and its 11-oxo derivatives.

Synthesis and structural characterization of new esters of oleanolic acid and its 11-oxo derivatives are reported. Compounds crystallize in four isostructural groups, each containing one to four structures. Single-crystal X-ray analysis revealed that molecules belonging to non-isostructural groups self-associate according to two schemes that describe also supramolecular architectures in crystals of glycyrrhetinic acid derivatives. Structural motifs arise as a result of van der Waals forces. Parameters introduced for the analysis of one- and two-dimensional assemblies allow the comparison of motifs in isostructural and non-isostructural crystals, including polymorphs, and a qualitative assessment of differences in molecular self-assembly. One-, two- or three-dimensional similarity has been confirmed by XPac calculations.

Selected plant triterpenoids and their amide derivatives in cancer treatment: A review.

Medicinal plants have been used to treat different diseases throughout the human history namely in traditional medicine. Most of the plants mentioned in this review article belong among them, including those that are widely spread in the nature, counted frequently to be food and nutrition plants and producing pharmacologically important secondary metabolites. Triterpenoids represent an important group of plant secondary metabolites displaying emerging pharmacological importance. This review article sheds light on four selected triterpenoids, oleanolic, ursolic, betulinic and platanic acid, and on their amide derivatives as important natural or semisynthetic agents in cancer treatment, and, in part, in pathogenic microbe treatment. A literature search was made in the Web of Science for the given key words covering the required area of secondary plant metabolites and their amide derivatives. The most recently published findings on the biological activity of the selected triterpenoids, and on the structures and biological activity of their relevant amide derivatives have been summarized therein. Mainly anti-cancer effects, and, in part, antimicrobial and other effects of the four selected triterpenoids and their amide derivatives have also been reviewed. A comparison of the effects of the parent plant products and those of their amide derivatives has been made.

Recent advances in medicinal chemistry of oleanolic acid derivatives.

Oleanolic acid (OA), a ubiquitous pentacyclic oleanane-type triterpene isolated from edible and medicinal plants, exhibits a wide spectrum of pharmacological activities and tremendous therapeutic potential. However, the undesirable pharmacokinetic properties limit its application and development. Numerous researches on structural modifications of OA have been carried out to overcome this limitation and improve its pharmacokinetic and therapeutic properties. This review aims to compile and summarize the recent progresses in the medicinal chemistry of OA derivatives, especially on structure-activity relationship in the last few years (2010-2021). It gives insights into the rational design of bioactive derivatives from OA scaffold as promising therapeutic agents.