The N-Alkylation of Agelastatin A Modulates Its Chemical Reactivity.

Agelastatin A is a marine alkaloid with potent biological activity. To date, at least 17 different strategies have achieved its total synthesis, along with many analogues. The present study focuses on the acidity stability of some N-methyl derivatives of agelastatin A. The study made use of chemical reactions and spectroscopic acquisitions. The chemical structure of some derivatives can undergo a profound rearrangement. The results could shed light on the mechanism of action of agelastatin A and suggest the preparation of analogues with improved pharmacological efficacy.

Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon-like peptide-1 receptor agonists. A multicenter retrospective longitudinal study.

AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is common in people with type 2 diabetes (T2D) and can progress to advanced fibrosis and cirrhosis. In this retrospective study, we explored the longitudinal changes in markers of hepatic steatosis and fibrosis during T2D treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). METHODS: We analysed observational data from six diabetes outpatient clinics. In the whole T2D population, we calculated the hepatic steatosis index (HSI), which we previously validated against liver ultrasonography, and the Fibrosis (Fib)-4 index. We then identified patients who initiated a GLP-1RA from 2010 to 2018 and for whom data were available to evaluate changes in both HSI and Fib-4 scores over 24 months. RESULTS: From 83,116 outpatients with T2D, 41,302 (49.7%) had complete data for calculating HSI and Fib-4. Most of these T2D patients (∼70%) had MAFLD (defined as HSI>36), 9.7% of whom had advanced fibrosis based on Fib-4 thresholds. Patients with low compared to high risk of advanced fibrosis were 5-times more likely to be treated with GLP-1RA. In 535 patients who initiated a GLP-1RA, the prevalence of MAFLD based on HSI declined significantly at 6 and 24 months, but Fib-4 categories did not. HSI improved significantly only in patients receiving human-based but not exendin-based GLP-1RA, while patients concomitantly receiving metformin had less worsening in Fib-4 categories. CONCLUSIONS: MAFLD is very common among outpatients with T2D (∼70%) and the estimated prevalence of advanced fibrosis was ∼10%. Treatment with GLP-1RAs significantly improved MAFLD, but not MAFLD-associated advanced fibrosis.

Fixed versus flexible combination of GLP-1 receptor agonists with basal insulin in type 2 diabetes: A retrospective multicentre comparative effectiveness study.

BACKGROUND AND AIMS: The combination of basal insulin (BI) and GLP-1 receptor agonists (GLP-1RAs) is a rational and effective therapy for patients with uncontrolled type 2 diabetes (T2D). We compared the effectiveness of fixed and flexible BI/GLP-1RA combinations using routinely accumulated clinical data. METHODS: This was a retrospective, multicentre, real-world study concerning T2D patients initiating a fixed or flexible BI/GLP-1RA combination (NCT03959865). The primary endpoint was change in HbA1c. Secondary endpoints were changes in body weight, fasting plasma glucose (FPG) and systolic blood pressure (SBP). Confounding was addressed by propensity score matching (PSM) or multivariable adjustment (MVA). RESULTS: A total of 609 patients were included in the study, 131 in the fixed group and 478 in the flexible group. The two groups differed in terms of diabetes duration, body weight and concomitant medications. After 5.7 months, observed HbA1c reductions were 0.6% and 0.8%, and body weight reductions were 2.8 kg and 1.2 kg in the flexible and fixed groups, respectively. Following PSM, HbA1c declined similarly in the two groups, whereas reduction in body weight was significantly in favour of the flexible combination. Findings were robust in sensitivity analyses, with the exception that, with MVA, a significantly higher reduction in HbA1c was detected in the fixed group. Final doses of BI were higher in the fixed group, whereas those of GLP-1RA were higher in the flexible group. CONCLUSIONS: In routine specialist care, initiation of the fixed or flexible BI/GLP-1RA combination allowed similar improvement in glycaemic control, but greater weight loss was observed with the flexible combination. This difference reflected dosages of BI and GLP-1RAs.

Longitudinal Structure-Function Evaluation in a Patient with CDHR1-Associated Retinal Dystrophy: Progressive Visual Function Loss with Retinal Remodeling.

BACKGROUND: Retinal dystrophies related to damaging variants in the cadherin-related family member 1 (CDHR1) gene are rare and phenotypically heterogeneous. Here, we report a longitudinal (three-year) structure-function evaluation of a patient with a CDHR1-related retinal dystrophy. METHODS: A 14-year-old girl was evaluated between 2019 and 2022. An ophthalmological assessment, including color vision, perimetry, electroretinography, and multimodal imaging of the retina, was performed periodically every six months. Next-generation sequencing disclosed two likely pathogenic/pathogenic variants in the CDHR1 gene, in compound heterozygosity, confirmed by segregation analysis. RESULTS: At first examination, the patient showed a cone-rod pattern retinal dystrophy. Over follow-up, there was a decline of visual acuity and perimetric sensitivity (by ≥0.3 and 0.6 log units, respectively). Visual loss was associated with a progressive increase in inner retinal thickness (by 30%). Outer retina showed no detectable changes over the follow-up. CONCLUSIONS: The results indicate that, in this patient with a CDHR1-related cone-rod dystrophy, the progression to severe visual loss was paralleled by a progressive inner retinal thickening, likely a reflection of remodeling. Inner retinal changes over time may be functionally relevant in view of the therapeutic attempts based on gene therapy or stem cells to mitigate photoreceptor loss.

Long-Term Structural and Functional Assessment of Doyne Honeycomb Retinal Dystrophy following Nanosecond 2RT Laser Treatment: A Case Series.

Introduction: Doyne honeycomb retinal dystrophy (DHRD), or autosomal dominant radial drusen, is a genetic disease caused by pathogenic variants of the epidermal growth factor (EGF)-containing fibulin-like extracellular matrix protein 1 EFEMP1 gene and is characterized by the formation of subretinal drusenoid deposits. In a previous study, we reported the short-term beneficial effects of nanosecond laser treatment (2RT) on retinal function in DHRD. The aim of the present report was to describe the findings of a long-term follow-up of retinal structure/function in a small case series of patients with DHRD who underwent 2RT treatment. Case Presentation: Three DHRD patients (case 1, male and cases 2 and 3, two sister females, age range 41-46) with EFEMP1 pathogenic variant (c.1033C>T; p.R345W) and drusenoid deposits at the posterior pole were examined at baseline and after 2RT treatment, at regular intervals (every 2-4 months) up to 30 months. All 3 patients underwent one or two treatment sessions in one or both eyes during the follow-up period. Case 3 was treated with only the left eye (LE). Each patient underwent a full ophthalmologic examination, spectral domain optical coherence tomography (OCT), central perimetry with frequency doubling technology, and mesopic and photopic Ganzfeld electroretinograms. Compared to baseline findings, during follow-up, visual acuity improved in both eyes in case 1 and LE in case 2, while it decreased in the right eye in case 2 and LE in case 3; perimetric sensitivity was stable in case 1 and improved in both eyes in cases 2 and 3; and electroretinogram amplitude improved in cases 1 and 2 and was stable in case 3 (both eyes). OCT central macular thickness and retinal structure were stable in all cases. None of the patients had treatment-related side effects. Conclusion: This is the first report showing that in a long-term follow-up, 2RT treatment in DHRD may improve or stabilize some retinal function parameters without significant structural changes.

Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the ß-Catenin Armadillo Repeats Domain as an Anticancer Agent.

Despite intensive efforts, no inhibitors of the Wnt/ß-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel N-(heterocyclylphenyl)benzenesulfonamides as ß-catenin inhibitors. Compounds 5-10 showed strong inhibition of the luciferase activity. Compounds 5 and 6 inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound 9 induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT116. In a co-immunoprecipitation study in HCT116 cells transfected with Myc-tagged T-cell factor 4 (Tcf-4), compound 9 abrogated the association between ß-catenin and Tcf-4. The crystallographic analysis of the ß-catenin Armadillo repeats domain revealed that compound 9 and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound 9 is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of ß-catenin inhibitors as anticancer agents.

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/ß-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells.

We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/ß-catenin signaling pathway. The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 (Ki = 6.8 nM) suppressed the Wnt/ß-catenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved caspase-3. Compound 15 showed strong inhibition of viability in a panel of cancer cells, including colorectal cancer and triple-negative breast cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15 is a novel dual-targeting compound with activity against hCA and Wnt/ß-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.

Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor.

We synthesized new aroyl diheterocyclic pyrrole (ARDHEP) 15 that exhibited the hallmarks of ferroptosis. Compound 15 strongly inhibited U-87 MG, OVCAR-3, and MCF-7 cancer cells, induced an increase of cleaved PARP, but was not toxic for normal human primary T lymphocytes at 0.1 µM. Analysis of the levels of lactoperoxidase, malondialdehyde, lactic acid, total glutathione, and ATP suggested that the in vivo inhibition of cancer cell proliferation by 15 went through stimulation of oxidative stress injury and Fe2+ accumulation. Quantitative polymerase chain reaction analysis of the mRNA expression in U-87 MG and SKOV-3 tumor tissues from 15-treated mice showed the presence of Ptgs2/Nfe2l2/Sat1/Akr1c1/Gpx4 genes correlated with ferroptosis in both groups. Immunofluorescence staining revealed significantly lower expressions of proteins Ki67, CD31, and ferroptosis negative regulation proteins glutathione peroxidase 4 (GPX4) and FTH1. Compound 15 was found to be metabolically stable when incubated with human liver microsomes.

Deintensification of basal-bolus insulin after initiation of GLP-1RA in patients with type 2 diabetes under routine care.

AIMS: We evaluated de-intensification of basal-bolus insulin (BBI) after initiation of a GLP-1 receptor agonist (GLP-1RA) under routine care. RESEARCH DESIGN AND METHODS: This retrospective, multicenter study conducted at outpatient clinics in North-East Italy collected data on patients with T2D on BBI who initiated a GLP-1RA. Patients were divided according to whether they de-intensified BBI at the end of observation by stopping prandial insulin. RESULTS: We included 425 patients with mean age of 61.3 years and 13 years of diabetes duration. Baseline HbA1c was 8.6% and BMI was 35.5 kg/m2. After 14 months. 58.6% of patients de-intensified BBI after initiating GLP-1RA: they were younger, had a shorter disease duration, lower HbA1c and insulin dose, and less frequent microangiopathy than those who continued BBI. A probability estimation based on these variables was validated in an independent cohort of 40 patients. Body weight improved in both groups, but HbA1c and fasting plasma glucose significantly declined only among patients who de-intensified BBI. Patients who de-intensified BBI and persisted on GLP-1RA at the last observation (80.7%) had greater HbA1c reductions. CONCLUSION: Under routine care, GLP-1RA initiation frequently allowed discontinuing BBI, especially among patients with shorter disease duration, lower insulin requirement, and better glucose control.

Minor acetylated metabolites from Euphrasia rostkoviana.

The phenylethanoids rostkovianoside, 6'-O-acetylcrassifolioside and the flavonoid rutin 3‴-acetate, were isolated from the methanolic extract of the aerial parts of Euphrasia rostkoviana Hayne. The structures of these previously undescribed compounds were elucidated by interpretation of spectroscopic data. The acetylation of rutin was also carried out and four ester derivatives were spectroscopically characterized. Finally, a chromatographic method was established to easily identify the acetylated position.

Effectiveness of dulaglutide vs liraglutide and exenatide once-weekly. A real-world study and meta-analysis of observational studies.

INTRODUCTION AND AIM: Real-word data on the head-to-head comparisons among glucagon-like peptide-1 receptor agonists (GLP-1RA) are scant. Therefore, we aimed to compare the effectiveness of dulaglutide versus liraglutide and exenatide once weekly (exeOW) in type 2 diabetic (T2D) patients under routine care. METHODS: This was a retrospective, multicenter, real-world study on patients with T2D (aged 18-80) initiating a GLP-1RA between 2010 and 2018 at specialist outpatient clinics. We compared the effectiveness of dulaglutide versus liraglutide and exeOW on the changes in HbA1c (primary outcome), body weight, blood pressure and fasting glucose (secondary outcomes). Average follow-up was 5.9 months. Channelling biases were addressed with propensity score matching or multivariable adjustment. Meta-analyses of observational studies, covering the same comparisons, are also presented. RESULTS: 849, 1371 and 198 patients were included in the dulaglutide, liraglutide and exeOW groups, respectively. The reduction of HbA1c was greater with dulaglutide than with liraglutide (-0.24 ±â€¯0.08%; p = 0.003), and was confirmed in the meta-analysis of observational studies. In our study, dulaglutide showed similar effectiveness compared to exeOW. When these results were pooled with other observational studies, dulaglutide showed a greater reduction of HbA1c (-0.19%; p = 0.003) and body weight (-0.8 kg; p = 0.007). CONCLUSIONS: In a real-world scenario, dulaglutide reduced HbA1c more than liraglutide. Conversely, we found similar effect of dulaglutide and exeOW, with statistical differences arising solely when results were meta-analysed with those from other observational studies. Lack of up-titration for liraglutide and higher discontinuation rate for exeOW likely influenced the estimated treatment difference.

Effectiveness of Dulaglutide in the Real World and in Special Populations of Type 2 Diabetic Patients.

CONTEXT: In randomized controlled trials (RCTs) on type 2 diabetes (T2D) patients, the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-RA) dulaglutide reduced HbA1c and body weight, but generalizability of such findings to real-world T2D patients is challenging. OBJECTIVE: We evaluated effectiveness of dulaglutide in routine clinical practice, especially in subgroups of patient that are underrepresented in RCTs. DESIGN: Retrospective multicenter study. SETTING: Diabetes outpatient clinics. PATIENTS AND INTERVENTION: All consecutive patients who initiated dulaglutide between 2015 and 2018. MAIN OUTCOME MEASURES: Changes in HbA1c and body weight were assessed up to 30 months after baseline. Effectiveness was analyzed in patient subgroups according to: prior use of GLP-1RA, persistence on treatment and dose, age, sex, disease duration, renal function, obesity, cardiovascular disease, or concomitant use of insulin or sulphonylurea. RESULTS: From a background population of 83,116 patients, 2084 initiated dulaglutide (15.3% switching from another GLP-1RA), 1307 of whom had at least 1 follow-up visit. Overall, dulaglutide reduced HbA1c by 1.0% and body weight by 2.9 kg at the end of observation. These effects were more pronounced in GLP-1RA-naïve patients and in those with shorter disease duration. Improvement in HbA1c was highly significant and consistent across all subgroups, including those aged ≥ 75 years, nonobese, or with chronic kidney disease. Body weight declined in all subgroups and significantly more with the 1.5-mg versus 0.75-mg dose. CONCLUSIONS: In real-world T2D patients, effectiveness of dulaglutide on HbA1c and body weight reduction was highly consistent and significant even in subgroups of patients poorly represented in RCTs.

Trend 2010-2018 in the clinical use of GLP-1 receptor agonists for the treatment of type 2 diabetes in routine clinical practice: an observational study from Northeast Italy.

AIMS: Several GLP-1 receptor agonists (GLP-1RA) have become available for the treatment of type 2 diabetes (T2D), and evidence on their beneficial effects has evolved. We evaluated how the clinical phenotype of patients initiating GLP-1RA changed from 2010 to 2018. METHODS: This was a retrospective study conducted at six diabetes outpatient clinics in Northeast Italy. We collected data of T2D patients who initiated new GLP-1RA between 2010 and 2018. We recorded baseline characteristics, including demographics, anthropometrics, cardiovascular risk factors, glucose control, lipid profile, liver enzymes, renal function and concomitant medications. We recorded updated HbA1c and body weight at follow-up. RESULTS: There were 83,116 T2D patients from a general population of ~ 1,380,000 inhabitants. Among 6167 cases of GLP-1RA initiation, 5408 were analyzed after excluding intra-class switchers. Prescription of GLP-1RA increased exponentially, and the change in the type of GLP-1RA reflected waves of their entering the market. From 2010 to 2018, there were significant increases in baseline age, diabetes duration and prevalence of male sex, of cardiovascular disease and of insulin users. Blood pressure and cholesterol levels decreased concomitantly with increasing use of medications for the control of cardiovascular risk. Baseline average HbA1c (8.3% [67 mmol/mol]) and BMI (34 kg/m2) and their improvement after GLP-1RA initiation did not change over time. CONCLUSIONS: Despite the early positioning of GLP-1RA in T2D treatment algorithms, GLP-1RA have been prescribed in patients with progressively more advanced disease stage and especially in the presence of cardiovascular disease. Optimization of GLP-1RA use in routine clinical practice is still needed.

Inhibition of NF-kB and metalloproteinase-9 expression and secretion by parthenolide derivatives.

Semisynthetic derivatives of parthenolide (1) were tested on NF-kB driven transcription and metalloproteinase-9 (MMP-9) expression and secretion. The four membered ring compounds 5 and 6, obtained by acidic treatment of 1, exhibited a higher activity with respect to 1 in all the biological assays. Then an increased ability of the 5 and 6 to inhibit NF-kB driven transcription may lead to a down-regulation of MMP-9 expression and secretion. This work provides new details about the structural requisites for NF-kB inhibition.

Advances in the Dereplication of Aroma Precursors from Grape Juice by Pretreatment with Lead Acetate and Combined HILIC- and RP-HPLC Methods.

Glycosidic aroma precursors (GAPs) contribute to the varietal flavor of wine. Researchers have applied various sample preparation and analytical methods in attempts to achieve their separation and identification. However, mass spectrometric methods still fail to unequivocally define their structures. We have previously reported the separation of GAPs in their natural form and elucidated their structures by nuclear magnetic resonance (NMR) spectroscopy. In this study, we confirm the effectiveness of our established procedure and present methodological improvements. Grape juice was treated with lead (II) acetate and repeatedly chromatographed to give seven pure GAPs. Their chemical structures were characterized by MSn fragmentations and 1D- and 2D-NMR spectra. Ten GAPs were analyzed by both hydrophilic interaction liquid chromatography (HILIC) and reversed phase high performance liquid chromatography (RP-HPLC) to compare the two chromatograms. A selection of known phenols was treated with lead (II) acetate in order to check its binding properties.

Clinical Impact of 5 Years of Liraglutide Treatment on Cardiovascular Risk Factors in Patients with Type 2 Diabetes Mellitus in a Real-Life Setting in Italy: An Observational Study.

INTRODUCTION: Based on existing data regarding the durability of liraglutide in type 2 diabetes, this study aimed to assess its long-term effectiveness at 5 years and its overall impact on cardiovascular (CV) risk. METHODS: This was a multicenter retrospective observational study. Liraglutide was used under routine clinical practice conditions. Changes from baseline to 60 months in HbA1c, fasting plasma glucose (FPG), body weight, blood pressure, and lipid profile were assessed. United Kingdom Prospective Diabetes Study (UKPDS) scores were calculated at baseline and after 60 months to assess changes in the estimated 5- and 10-year risk for fatal and nonfatal coronary heart disease (CHD) and fatal and nonfatal stroke. RESULTS: Overall, 103 patients (age 59.0 ± 7.9 years, diabetes duration 10.4 ± 6.8 years) were involved in the study. After 60 months, HbA1c levels were reduced by - 1.0 ± 1.2%, FPG levels by - 24.5 ± 43.4 mg/dl, body weight by - 5.3 ± 6.4 kg, systolic blood pressure by - 6.5 ± 18.5 mmHg, diastolic blood pressure by - 3.6 ± 11.8 mmHg, and total cholesterol by - 16.9 ± 37.4 mg/dl. The proportion of patients achieving HbA1c levels of < 7% increased from 12.7% to 39.8% (p = 0.02). Based on the UKPDS scores, statistically significant reductions in the 5- and 10-year risk of nonfatal CHD and fatal CHD were found, with no change in the 5- and 10-year risk of fatal and nonfatal stroke. CONCLUSION: In patients prolonging treatment with liraglutide for 5 years, the benefits in relation to metabolic control and CV risk factors are maintained. The UKPDS risk scores suggest that liraglutide is associated with a reduced CHD risk, but not with a reduced stroke risk.

Research survey on iridoid and phenylethanoid glycosides among seven populations of Euphrasia rostkoviana Hayne from the Alps.

The traditional use of extracts of Euphrasia rostkoviana to relieve ocular inflammation or infections is well documented and supported by clinical studies. Various classes of chemical compounds such as iridoids, phenylethanoids, flavonoids and hydroxycinnamic acids have been reported. The present work aims to assess the chemical diversity among seven populations of Euphrasia rostkoviana found in northern Italy. A meticulous separation of components led to the isolation and structural characterization of two previously unrecorded phenylethanoids methoxycrassifolioside and deoxycrassifolioside and one previously undescribed terpene glucoside (1E,6E)-8-hydroxy-3,7-dimethyl-octa-1,6-dienyl 1-O-ß-D-glucopyranoside. We have also identified known phenylethanoids and iridoids that are reported in this genus for the first time. Finally, a targeted quantitative analysis for the standardization of herbal preparations revealed that iridoids occur in all populations whereas the presence and the levels of rutin and phenylethanoids are highly variable.

Mastering analytical challenges for the characterization of pentacyclic triterpene mono- and diesters of Calendula officinalis flowers by non-aqueous C30 HPLC and hyphenation with APCI-QTOF-MS.

Pentacyclic triterpene mono- and diesters have been isolated from Calendula officinalis flowers. GC-MS, APCI-Exactive Orbitrap HR-MS and NMR allowed to identify the triterpene skeleton in various samples (different triterpene mixtures from Calendula n-hexane extract). NMR provided evidence that triterpene diesters are present in the samples as well. However, the corresponding quasi-molecular ions could not be detected by APCI-Exactive Orbitrap HR-MS. Instability of triterpene diesters and loss of a fatty acid residue, respectively, in the ion-source made their MS detection challenging. Thus, a set of new APCI-QTOF-MS methods (using the TripleTOF 5600+ mass spectrometer) were developed which made it eventually possible to solve this problem and confirm the diester structures by MS via quasi-molecular ion [M+H](+) detection. Direct infusion APCI-QTOF MS experiments in MS/MS high sensitivity scan mode with low collision energy and multi-channel averaging acquisition (MCA) allowed the detection of quasi-molecular ions of triterpene diesters for the first time and unequivocally confirmed the presence of faradiol 3,16-dimyristate and -dipalmitate, as well as the corresponding mixed diesters faradiol 3-myristate,16-palmitate and faradiol 3-palmitate,16-myristate. Preferential loss of the fatty acid in 16-position made it possible to distinguish the mixed diesters by MS/MS spectra. Their chromatographic separations turned out to be challenging due to their bulkiness and extended molecular dimensions. However, separation could be achieved by an uncommon non-aqueous RPLC mode with an in-house synthesized C30 phase. Finally, two (U)HPLC-APCI-QTOF-MS methods with C18- and C30-based non-aqueous RPLC provided suitable, sensitive assays to monitor the presence of monoesters and diesters of various triterpenes (faradiol, maniladiol, arnidiol, arnitriol A and lupane-3ß,16ß,20-triol esters) in the n-hexane extract of C. officinalis with high mass resolution and good mass accuracy.

Tirucallane triterpenes from the leaf extract of Entandrophragma angolense.

From the leaves of Entandrophragma angolense, three triterpenoidal compounds were isolated and structurally elucidated by mass and NMR spectroscopy. They belong to the tirucallane group but two of them possess the rare seco-ring-A feature. The phytochemical data are discussed from a chemotaxonomic and biogenetic points of view.

Improved anti-inflammatory activity of three new terpenoids derived, by systematic chemical modifications, from the abundant triterpenes of the flowery plant Calendula officinalis.

Rings A, D and E of faradiol (1), and ring E of both arnidiol (10) and calenduladiol (4) have been subjected to various selective chemical manipulations to modify polarity, water affinity, H-bonding, sterics, and number of aromatic groups of these anti-inflammatory natural compounds. A total of 15 new and four known pentacyclic triterpenoids have been obtained in this way. Some 13 terpenoids were evaluated for their topical anti-inflammatory activities with respect to inhibition of croton oil induced ear oedema in mouse. Three derivatives of 1, the C(16) benzyl ether 15, the C(30) aldehyde 24, and the C(30) primary alcohol 25 showed significantly improved anti-inflammatory potencies, which is relevant for (future) structure-activity-relationship (SAR) studies.