Michael acceptors, such as chalcones and benzylidenes, are privileged scaffolds for the development of anticancer agents. Taking this into account, we developed a selective Claisen-Schmidt condensation of the dammarane-type triterpenoid hollongdione with pyridine-2-carbaldehyde, enabling controlled synthesis of mono- and bis-substituted triterpenes depending on the reaction conditions. The reaction demonstrated high temperature-dependent regioselectivity, providing C2-mono- 2 or 2,21-bis-substituted 3 triterpenes with yields up to 96% and 95%, respectively. The structures of the newly synthesized triterpene chalcones were elucidated by 1D and 2D NMR spectroscopy and unambiguously confirmed by a single-crystal X-ray diffraction, which established the E configuration of the exocyclic double bond. In biological studies, the bis-2-pyridylidene derivative 3 exhibited a pronounced and broad-spectrum antitumor activity in the NCI-60 panel, inducing cell death in 58 of 59 cancer cell lines. High selectivity toward melanoma, renal, and prostate cancer cell lines was observed, with selectivity indices (SI) of up to 18.82 for melanoma LOX IMVI. In MTT assays, compound 3 displayed a submicromolar cytotoxicity, particularly against the KRAS-mutant PANC-1 cell line (IC50 = 0.22 µM). Anticancer activity was further confirmed in a zebrafish (Danio rerio) xenograft model of human HCT116 colon cancer, where tumor growth inhibition reached 72% without pronounced embryotoxicity (LC50 = 1.4 µM). We have developed an efficient approach for the site-selective modification of hollongdione, providing access to potent anticancer dammarane-type chalcones. The bis-2-pyridylidene derivative 3 emerged as a promising lead compound, demonstrating submicromolar potency, high selectivity towards melanoma, and significant in vivo efficacy in a zebrafish xenograft model.

An efficient multistep synthesis of novel substituted pyrazoline derivatives linked to a dammarane scaffold was developed for the first time. Initially, ozonolysis of one of the main metabolites of Dipterocarpus alatus - 3β-hydroxy-dipterocarpol afforded natural 3β-hydroxy-hollongdione, which was subsequently subjected to a Claisen-Schmidt condensation to furnish a derivative bearing a [3-(pyridin-2-yl)-prop-2-en-1-one]-fragment at C17 and the E-configuration of the double bond was confirmed by spectral analysis. Cycloaddition of the enone intermediates with formyl or acetyl hydrazides produced a mixture of S- and R-diastereomers in a 55:45 ratio, which were successfully separated by HPLC. The most prominent distinguishing feature between the R- and S-isomers was the chemical shift of the H-17 proton, appearing at δ 2.62 and δ 2.67, respectively. Additionally, the R-isomer exhibited a more downfield resonance for the Ha-3' proton and a relatively upfield shift for the Hb-3' proton.

The synthesis and multi-step spectroscopic characterization of diastereomeric 3-spiro-1,2,4-trioxolanes obtained by Griesbaum co-ozonolysis of sitostanone O-methyl oxime with two types of fluorinated ketones are reported. The reaction furnished four possible diastereomers that differ in the α/β orientation of the peroxide bridge relative to the steroid A-ring and in the syn/anti orientation of the trifluoromethyl group at C5′. A chemometric PLS2 approach, linking experimental and DFT-calculated 13C chemical shifts, was used for the objective stereochemical assignment of each diastereomer in the inseparable mixtures. Single-crystal X-ray analysis of the isolated 3R,5′R and 3R,5′S stereoisomeric pair (α-anti and α-syn ozonides) provided unambiguous absolute configurations that validated the stereochemical assignments obtained by the combined NMR/DFT/PLS2 approach. This integrated synthetic, crystallographic, spectroscopic, and chemometric methodology provides reliable configurational assignment in complex spiro-peroxide mixtures and expands the analytical toolkit for such systems.

Bile acids provide a versatile platform for the design of biologically active compounds due to their amphiphilic structure, biocompatibility, and capacity for diverse chemical modifications. Among them, lithocholic acid is a promising scaffold for designing and revealing new antiviral agents. A novel lithocholic acid-based 3-spiro-1,2,4-trioxolane was synthesized by Griesbaum co-ozonolysis of methyl 3-O-methyl-oximino-lithocholate and 4-(trifluoromethyl)-cyclohexanone, and its structure was confirmed by 2D NMR and X-ray crystallographic analysis. Lithocholic acid derivatives were evaluated for cytotoxicity and anti-influenza activity against A/Puerto Rico/8/34 (H1N1), showing that steroid 1,2,4-trioxolane 3 exhibited the highest potency (IC50 4.3 µM, SI 11) compared to the parent methyl-3-oxo-lithocholate 1 (IC50 > 84 µM, SI 1). In silico ADME predictions revealed several favorable drug-like properties, including a highly three-dimensional structure (Fsp3 = 0.97), significant lipophilicity (LogP = 7.54), and the presence of key pharmacophores such as a peroxide moiety and a trifluoromethyl group. Taken together, a stereospecific synthesis of a lithocholic acid 3-spiro-1,2,4-trioxolane by Griesbaum co-ozonolysis was realized and the first evidence of anti-influenza activity in the steroid-1,2,4-trioxolane series was found.

New 2-oxo-triterpenoids of ursane, dammarane and oleanane types were synthesised from the corresponding 3-oxo-derivatives by Willgerodte-Kindler reaction with yields of 31-42%. It was shown that their C2-oximes are formed as the equimolar mixtures of syn/anti-isomers in contrast to literature data for C3-oximes giving a single E-isomer due to the steric factors. The structures of 2-oxo- and 3-oxo-28-oxo-allobetulones as well as allobetulone 2E-oxime were confirmed by X-ray diffraction analysis. A regioisomer of natural erythrodiol - olean-12(13)-ene-2β,28-diol 19 was firstly synthesised by the reduction of methyl 2-oxo-oleanoate. The tested triterpenoids were more potent in α-glucosidase (from S. cerevisia) inhibition than acarbose (from 5 to 20 times). Erythrodiol 20 showed IC50 value of 8.35 μM, while it's regioisomer 19 was found as the most active and non-cytotoxic in terms of enzyme inhibition with an IC50 value of 14.19 μM.

From the leaves, twigs, and fruits of Helicia petelotii collected from the Hoang Lien mountain range in Sapa, Vietnam, six compounds were isolated including β-sitosterol (1), daucosterol (2), 3-O-[β-D-(6'-nonadecanoate)glucopyranosyl]-β-sitosterol (3), β-arbutin (4), breynioside B (5), and glycerol monostearate (6). Among them, compounds 3 and 6 were isolated from the fruits, while compounds 1, 2, 4, and 5 were obtained from the leaves and twigs. Advanced spectroscopic methods such as NMR and HR-ESI-MS were applied to accomplish the structures identification of the above compounds. The anti-denge potential of compounds 1-6 were examined against two dengue virus serotypes, DENV-1 and DENV-2. Among them compounds 3 and 5 demonstrated inhibitory activity against DENV-2, with PNRT₅₀ values of 18.25 µM and 159.43 µM, respectively, while the remaining compounds were inactive against all the virus serotypes. This is the first report of phytochemicals and antiviral properties of Helicia petelotii against Dengue virus.

A series of lupane, oleanane and ursane furoyloxy-triterpenoids were synthesised via acylation with 2-furoyl chloride and subsequently tested for anti-influenza activity against the pandemic influenza virus A/Puerto Rico/8/1934 (H1N1). Among them, 3β-furoyloxy-oleanolic and 3β-furoyloxy-ursolic acids were the most potent with IC50 values 17 and 1 µM with selectivity indexes of 32 and 26, respectively. The molecular structure of compound 11 was determined by X-ray diffraction analysis.

A series of 3 beta-furoyloxy-oleanolic acid derivatives modified at C-28 by linear and cyclic amines was synthesized and evaluated for antiviral properties. The 3 beta-furoyloxy-oleanolic acid spermidine amide 2 exhibited potent inhibition of influenza viruses, with IC50 values of 20 mu M (SI 22) against A/Puerto Rico/8/1934 (H1N1) and 12 mu M (SI 38) against A/Mallard/Pennsylvania/1984 (H5N2). Structure-activity relationship analysis revealed that introduction of a furoyloxy-group at C-3 improves selectivity, while spermidine conjugation at C-28 confers broad-spectrum activity with low toxicity. In contrast, substitution with cyclic amines (cyclohexylamine, N-methylpiperazine, morpholine) significantly reduced activity and increased cytotoxicity. Time-of-addition assays demonstrated that compound 2 acts at the early stage of the viral cycle by interfering with hemagglutinin (HA)-mediated attachment. Molecular docking supported binding near the HA fusion peptide with favorable complexation energy (213 kcal/mol). These results identify the 3 beta-furoyloxy-oleanolic acid spermidine amide moetiy as a key pharmacophore for developing new triterpenoid-based influenza entry inhibitors.

Dammarane triterpenoids are affordable and bioactive natural metabolites with great structural potential, which makes them attractive sources for drug development. The aim of the study was to investigate the potency of new dipterocarpol derivatives for the treatment of diabetes. Two dammaranes (dipterocarpol and its 20(24)-diene derivative) were modified by a Claisen-Schmidt aldol condensation to afford C2(E)-arylidenes in good yields. The majority of the synthesized compounds exhibited an excellent-to-moderate inhibitory effect toward alpha-glucosidase (from S. saccharomyces), among them eight compounds showed IC50 values less than 10 mu M. 3-Oxo-dammarane-2(E)-benzylidenes (holding p-hydroxy- 3 l and p-carbonyl- 3 m substituents) demonstrated the most potent alpha-glucosidase inhibition with IC(50 )0.753 and 0.204 mu M, being 232- and 857-times more active than acarbose (IC50 174.90 mu M), and a high level of NO inhibition in Raw 264.7 cells with IC50 of 1.75 and 4.57 mu M, respectively. An in vivo testing of compound 3 m (in a dose of 20 mg/kg) on a model of streptozotocin-induced T1DM in rats showed a pronounced hypoglycemic activity, the ability to reduce effectively the processes of lipid peroxidation in liver tissue and decrease the excretion of glucose and pyruvic acid in the urine. Compound 3 m reduced the death of diabetic rats and preserved their motor activity. image

Background Neuroinflammation contributes to degeneration of neurons in people with Parkinson's disease (PD). The concentrations of inflammatory cytokines, IL-1β, IL-6, and TNF-α, are often increased in people with PD and are associated with various non-motor symptoms. Qigong exercise is a mind-body practice which has been used as a rehabilitation intervention for people with PD. A previous study showed a strong association between sleep quality and inflammatory status. This study investigated the effect of Qigong on inflammatory status in people with PD and explored potential relationships between inflammatory status and sleep quality in this population. Methods The study was a randomized controlled trial. A total of 17 participants completed the 12-week intervention (Qigong (n = 8), sham Qigong (n = 9)). Questionnaires were utilized to assess non-motor symptoms, including sleep quality. Inflammatory cytokines were measured by a high sensitivity antibody-based multiplex assay. Results After the 12-week intervention, a decreasing trend in the concentrations of IL-1β and IL-6 was found in the Qigong group. Moderate to strong correlations were found between changes in IL-1β concentrations and sleep quality. Conclusion Inflammation is an important aspect of PD. This study explored the inflammatory status after a mind-body exercise. Further studies need to extend our findings to confirm the effect of Qigong in people with PD.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) - are depression and neurodegenerative diseases that target enzymes, including Alzheimer’s disease (AD). With the goal of searching for cholinesterase enzyme inhibitors, a series of four new and twelve previously modified at C2/С2,С21 (arylidenes) and C3 (acylates) positions of dipterocarpol compounds were evaluated for acetylcholinesterase (from electric eel) and butyrylcholinesterase (from equine serum) inhibitory activity. As a result, dammaranes with 3β-O-(2-furoyl)- 2, 2-(p-nitro-benzylidene)- 7, and 2,21-bis-(p-carbonylbenzylidene)- 17 fragments exhibited a pronounced activity with 79.0, 68.8 and 75.2

Allobetulin derivatives with rearranged E-ring exhibit important pharmacological properties against various viral pathogens. Basing on 3β-acetoxy-21β-acetyl-20β,28-epoxy-18α,19βH-ursane triterpenoid, obtained from allobetulin in one stage, a series of new derivatives have been synthesized and their antiviral activity against both influenza virus A (H1N1) and SARS-CoV-2 pseudovirus was evaluated. Among them, 2,3-indolo-allobetulone N-propargyl derivatives were the most efficacious against influenza virus with low toxicity (CC50 × 300 μM) and IC50 values of 7.04 to 3.5 μM and high selectivity indexes (SI 43 and 86). Compared with amodiaquine, a derivative with 3-pyridinylidene fragment 12 showed a weak antiviral activity against SARS-CoV-2 pseudovirus with an inhibition rate of 57.3

A series of messagenin-based chalcones has been synthesized by Claisen-Schmidt condensation and screened for in vitro alpha-glucosidase inhibitory activity. The heterocyclization of 30-(3-pyridinylidene)-messagenin led to syn/anti N-acetyl-pyrazoles in a ratio of 2 : 1 that were isolated by HPLC. Messagenin chalcones act as alpha-glucosidase inhibitors with IC50 range from 0.055 to 80.70 mu M. The lead nanomolar level alpha-glucosidase inhibitor 30-(4-hydroxymethyl-benzylidene)-messagenin 10 was studied for antihyperglycemic activity on streptozotocin-induced diabetic animal models using in vivo mechanism-based assays. In a rat model of STZ-induced T1DM, compound 10 (20 mg/kg, orally) exhibited antihyperlipidemic activity, reducing AIP (p>0.05) and CRI (p<0.05) compared to control. Compound 10 improved diabetic nephropathy, locomotor activity in rats, and reduced diabetes-related mortality.

By modifying ring A in the dammarane triterpenoid dipterocarpol, derivatives with isoxazole and 2-cyano-1-ene fragments were synthesized, which showed activity against the influenza A virus (H1N1) with selectivity indices of 19 and 23.

Hollongdione is the first recorded example of the occurrence of a dammarane hexanor-triterpene in nature possessing antiviral and cytotoxic activity. Its simple one-stage transformation into compounds with terminal alkyne and vinyl chloride fragments via the interaction with phosphorus halides is reported. The copper(I)-catalyzed Mannich reaction of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20(21)-in 3 led to a series of aminomethylated products, while 17-carboxylic acid was obtained by ozone oxidation of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20-chloro-20(21)-en 4; the following direct amidation of the latter has been developed. The structures of all new molecules were established by spectroscopic studies that included 2D NMR correlation methods; the molecular structures of compounds 2–5 were determined by X-ray analysis.

llobetulin derivatives with rearranged E -ring exhibit important pharmacological properties against various viral pathogens. Basing on 3 β -acetoxy-21 β -acetyl-20 β ,28-epoxy-18 α ,19 βH -ursane triterpenoid, obtained from allobetulin in one stage, a series of new derivatives have been synthesized and their antiviral activity against both influenza virus A (H1N1) and SARS-CoV-2 pseudovirus was evaluated. Among them, 2,3-indolo-allobetulone N -propargyl derivatives were the most efficacious against influenza virus with low toxicity (CC 50 × 300 μM) and IC 50 values of 7.04 to 3.5 μM and high selectivity indexes (SI 43 and 86). Compared with amodiaquine, a derivative with 3-pyridinylidene fragment 12 showed a weak antiviral activity against SARS-CoV-2 pseudovirus with an inhibition rate of 57.3% at a concentration of 20 μM. Further optimization to increase the cellular antiviral activity seems to be necessary to develop this series of triterpenoids as antiviral agents.

A set of triterpene A-ring hydroxymethylene-amino-derivatives was synthesized and their antiviral activity was studied. The synthesized compounds were tested for their potential inhibition of SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells and influenza A/PuertoRico/8/34 (H1N1) virus in MDCK cell culture. Compounds 6 , 8 and 19 showed significant anti-SARS-CoV-2 pseudovirus activity with EC 50 value of 3.20-11.13 µM, which is comparable to the positive control amodiaquine (EC 50 3.17 µM). Among them, 28- O -imidazolyl-azepano-betulin 6 and C3-hydroxymethylene-amino-glycyrrhetol-11,13 - diene 19 were identified as the lead compounds with SI values of 7 and 10. The binding mode of compound 6 into the RBD domain of SARS-CoV-2 spike glycoprotein (PDB code: 7DK3) by docking and molecular dynamics simulation was investigated.

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, chronic inflammation, impaired insulin secretion, and/or peripheral insulin resistance. Current α-glucosidase inhibitors approved for clinical use exhibit limited efficacy compared to other glucose-lowering agents. In this study, a series of mono- and bis-benzylidene derivatives were synthesized via aldol condensation of 3-oxo-dammarane triterpenoids with terephthalic aldehyde. The target mono- and bis-benzylidene derivatives, based on the dammarane triterpenoids hollongdione 1, (20S)-23,24-epoxy-25,26,27-trinordammar-3,24-dione 2, and 24(R,S)-20(S)-epoxy-25-hydroxy-dammar-3-one 3, were successfully synthesized. Several of these inhibitors demonstrated significantly greater efficacy than the reference drug acarbose. Notably, compound 4 inhibited S. cerevisiae α-glucosidase with an IC50 of 2.67 μM. Furthermore, the target compounds effectively inhibited NLRP3 inflammasome activation, reducing IL-1β production in LPS+ATP-stimulated murine peritoneal macrophages without detectable cytotoxicity. Compound 8, which exhibited dual activity, was further characterized as an inhibitor of NLRP3 activation in peripheral blood mononuclear cells, leading to the prevention of pyroptosis and IL-1β release. Additionally, compound 8 was shown to promote neuronal survival in LPS+ATP-treated rat hippocampal slices, highlighting its potential as a promising antidiabetic agent that targets both postprandial hyperglycemia and metaflammation.

Modification of oleanolic acid synthesized new N -containing derivatives with amino- and azepano-fragments in rings A and C that were highly active against C. trachomatis with a chemotherapeutic index > 8.

Purpose The purpose of this convergent mixed methods study was to assess the perceptions and characteristics of sleep in breast cancer survivors (BCSs) and elucidate perceptions of sleep among BCS with lymphedema. Methods Participants were BCS with and without lymphedema. Both groups completed the Pittsburgh Sleep Quality Index (PSQI), PROMIS® Sleep Disturbance (8a short form), and wore an actigraph on their wrist to capture sleep/wake cycles for 7 days/nights while logging their sleep using a sleep diary. The coefficient of variation of sleep efficiency was calculated from the sleep diary to assess intraindividual variability. In addition, a subsample of BCS with lymphedema participated in a semi-structured qualitative interview. The qualitative data was analyzed separately, and the themes were applied to provide a more nuanced explanation of the quantitative outcomes. Results The BCS with lymphedema ( n =23) had a significant difference in PSQI ( p =0.002), PROMIS® Sleep Disturbance ( p =0.084), and sleep efficiency coefficient of variation ( p =0.014) compared to BCS without lymphedema ( n =23). There were no statistically significant differences between groups in the actigraphy results. BCS with lymphedema perceived that lymphedema management contributed to their sleep disturbance, further exacerbating their mind/body fatigue. Conclusion This study provides the foundation for future research to investigate the integration of sleep interventions with lymphedema management for holistic survivorship care for BCS with lymphedema. Implications for Cancer Survivors An innovative sleep health intervention designed to consider the unique factors contributing to sleep disturbance in BCS with lymphedema will fill a gap in their post-cancer treatment quality of life.