Butyrolactone Lignans Research Articles

Machine-Learning- and Structure-Based Virtual Screening for Selecting Cinnamic Acid Derivatives as Leishmania major DHFR-TS Inhibitors.

The critical enzyme dihydrofolate reductase-thymidylate synthase in Leishmania major (LmDHFR-TS) serves a dual-purpose role and is essential for DNA synthesis, a cornerstone of the parasite's reproductive processes. Consequently, the development of inhibitors against LmDHFR-TS is crucial for the creation of novel anti-Leishmania chemotherapies. In this study, we employed an in-house database containing 314 secondary metabolites derived from cinnamic acid that occurred in the Asteraceae family. We conducted a combined ligand/structure-based virtual screening to identify potential inhibitors against LmDHFR-TS. Through consensus analysis of both approaches, we identified three compounds, i.e., lithospermic acid (237), diarctigenin (306), and isolappaol A (308), that exhibited a high probability of being inhibitors according to both approaches and were consequently classified as promising hits. Subsequently, we expanded the binding mode examination of these compounds within the active site of the test enzyme through molecular dynamics simulations, revealing a high degree of structural stability and minimal fluctuations in its tertiary structure. The in silico predictions were then validated through in vitro assays to examine the inhibitory capacity of the top-ranked naturally occurring compounds against LmDHFR-TS recombinant protein. The test compounds effectively inhibited the enzyme with IC50 values ranging from 6.1 to 10.1 μM. In contrast, other common cinnamic acid derivatives (i.e., flavonoid glycosides) from the Asteraceae family, such as hesperidin, isovitexin 4'-O-glucoside, and rutin, exhibited low activity against this target. The selective index (SI) for all tested compounds was determined using HsDHFR with moderate inhibitory effect. Among these hits, lignans 306 and 308 demonstrated the highest selectivity, displaying superior SI values compared to methotrexate, the reference inhibitor of DHFR-TS. Therefore, continued research into the anti-leishmanial potential of these C6C3-hybrid butyrolactone lignans may offer a brighter outlook for combating this neglected tropical disease.

The enantioselective total syntheses of (+)-7-oxohinokinin, (+)-7-oxoarcitin, (+)-conicaol B and (-)-isopolygamain.

A flexible approach to C7 keto dibenzyl butyrolactone lignans was developed and the synthesis of several natural products and their related derivatives is described herein. The developed pathway proceeds through enantioenriched β-substituted butyrolactones, from which facile aldol addition and subsequent oxidation affords the desired benzylic ketone moiety. This methodology was used to complete the first enantioselective total syntheses of three natural products, (+)-7-oxohinokinin, (+)-7-oxoarcitin and (+)-conicaol B, and a further five analogues. The utility of this method was further demonstrated through a 1-2 step modification to access another class of natural product, aryltetralin lignans, allowing the asymmetric total synthesis of (-)-isopolygamain and a polygamain derivative. Anti-proliferative testing determined (-)-isopolygamain was the most active of the compounds prepared, with IC50 values of 2.95 ± 0.61 μM and 4.65 ± 0.68 μM against MDA-MB-231 (triple negative breast cancer) and HCT-116 (colon cancer) cell lines, respectively.

Bioactive Lignans from Hypoestes aristata.

Phytochemical investigation of extracts of the stems of Hypoestes aristata led to the isolation of nine lignans that included four known compounds, namely, hinokinin (1), savinin (2), medioresinol (3), and two cubebins (8a,b), three new butyrolactone lignans (4-6), and butyrolactol lignans 7a-c. The structures of the new compounds were established using 1D and 2D NMR and HRESIMS data. The absolute configurations of the new lignans were determined from their ECD data and the Mosher's ester method. This is the first unequivocal assignment of the absolute configuration at C-7 and C-7' of 7- and 7'-hydroxybutyrolactone lignans. The compounds were screened for inhibition of an HIV-1 protease enzyme, and compounds 1 and 6 exhibited moderate activity in this regard.

Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans.

Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.

A New Method for Asymmetric Synthesis of (－)-Arctigenin and Its Enantiomer

Arctigenin, the main active ingredient of traditional chinese medicine (TCM) arctii fructus, belongs to diben- zyl butyrolactone lignans. In order to study the structure-activity relationship of arctigenin, a new method for asymmetric syn- thesis of (-)-arctigenin and its enantiomer was developed. Phenylpropanoic acid derivate was used as starting material and the chiral center of beta butyrolactone was constructed by using oxazolidinone chiral auxiliary. The ees of R and S configurations are 98% and 96%, respectively. Then the second chiral center in the alpha position was constructed benefitting from the steric effect. After removal of protecting group, the target compounds were obtained in 58 % and 55% overall yield of (-)-arcti- genin and (+)-arctigenin with 97% and 96% ee, respectively. This work paved the way for further structural optimization of

New Butyrolactone Type Lignans from Arctii Fructus and Their Anti-inflammatory Activities.

Arctiidilactone (1), a novel rare butyrolactone lignan with a 6-carboxyl-2-pyrone moiety, and 11 new butyrolactone lignans (2-12) were isolated from the fruits of Arctium lappa L., together with 5 known compounds (13-17). Their structures were elucidated by interpretation of their spectroscopic data (1D and 2D NMR, UV, IR, ORD, and HRESIMS) and comparison to literature data. The absolute configurations of compounds 1-12 were determined by a combination of rotating-frame nuclear Overhauser effect spectroscopy (ROESY), circular dichroism (CD) spectroscopy, and Rh2(OCOCF3)4-induced CD spectroscopy. All of the compounds were tested for their anti-inflammatory properties in terms of suppressing the production of NO in lipopolysaccharide-induced BV2 cells. Compounds 1, 6, 8, and 10 exhibited stronger anti-inflammatory effects than the positive control curcumin, particularly 1, which exhibited 75.51, 70.72, and 61.17% inhibition at 10, 1, and 0.1 μM, respectively.

Apoptosis inducing activity of benzophenanthridine-type alkaloids and 2-arylbenzofuran neolignans in HCT116 colon carcinoma cells

Thirteen compounds belonging to different classes of alkaloids (1–9) and lignans (10–13), isolated from the methanol extract of roots of the African medicinal plant Zanthoxylum capense, were assayed for their ability as apoptosis inducers in HCT116 colon carcinoma cells. The cytotoxicity of these compounds was evaluated in HCT116 colon carcinoma cells by the MTS assay. Out of the tested compounds, three benzophenanthridine alkaloids (1, 4, and 7), a dibenzyl butyrolactone lignan (10), and two 2-arylbenzofuran neolignans (12 and 13) displayed significant cytotoxicity to HCT116 cells, confirmed by the Guava ViaCount viability assay. The selected compounds (1, 4, 7, 10, 12, and 13) were further tested for apoptosis induction activity in HCT116 cells, by evaluation of nuclear morphology following Hoechst staining, and by caspase-3 like activity assays. Morphologic evaluation of HCT116 nuclei following Hoechst staining and fluorescence microscopy revealed that compounds 1, 4, 7, 10, 12, and 13 induced apoptosis in HCT116 colon carcinoma cells, producing similar, or higher, apoptosis levels when compared with 5-fluorouracil (5-FU), the cornerstone cytotoxic used in colon cancer treatment for several decades. In fact, HCT116 cells developed morphological changes characteristic of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. Importantly, compounds 4 and 13 at 20μM were the most promising in this study, inducing respectively ∼11- and 7-fold increases in apoptotic cells as compared to vehicle control, whereas 5-FU increased apoptosis by ∼2-fold. Apoptosis induction for compounds 4 and 13 was further confirmed by caspase-3-like activity assays, which showed respectively ∼2- and 1.5-fold increases in caspase-3-like activity compared to vehicle control. These results suggested that specific benzophenanthridine alkaloids and 2-arylbenzofuran neolignans isolated from Zanthoxylum capense show strong anticancer activity in HCT116 colon carcinoma cells.

Dibenzylbutane‐ and Butyrolactone‐type Lignans as Apoptosis Inducers in Human Hepatoma HuH‐7 Cells

Seven lignans, previously isolated from Pycnanthus angolensis or obtained by derivatization, namely the dibenzylbutane-type lignans threo-4,4'-dihydroxy-3-methoxylignan (1), 4'-hydroxy-3,3',4-trimethoxylignan (2), (-)-dihydroguaiaretic acid (3), 3,3',4,4'-tetramethoxylignan (4), 4,4'-diacetyl-3,3'-dimethoxylignan (5), heliobuphthalmin (6) and the butyrolactone lignan hinokinin (7), were evaluted for their ability as apoptosis inducers in human hepatoma HuH-7 cells. Cell viability assays, morphological evaluation of apoptosis and enzymatic analyses of caspase activity in HuH-7 cells were carried out. Using the lactate dehydrogenase lactate dehydrogenase (LDH) assay, it was demonstrated that the lignans (1-7) tested significantly reduced viability of HuH-7 cells. Morphologic evaluation of HuH-7 cells using Hoechst staining and fluorescence microscopy revealed that lignans 1-7 were strong inducers of apoptosis. In fact, HuH-7 cells developed morphological changes of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. However, lignans 2 and 7 were the most promising compounds in this study, inducing 2.4- and 2.5-fold increases in apoptotic cells as compared to controls. Caspase-3-like activity assays confirmed the morphologic data.

Complete assignments of 1H and 13C NMR spectral data for benzylidenebenzyl butyrolactone lignans

The structures of three benzylidenebenzyl butyrolactone lignans (gossypifan, carthamogenin, and savinin) have been established on basis of 1H NMR and 13C NMR spectroscopic data. The 1H NMR and 13C NMR spectra of these lignans have been fully assigned by the use of techniques such as gCOSY, non-edited gHSQC, and gHMBC. Complete assignment and most homonuclear hydrogen coupling constant measurements were performed, also providing enough data for the determination of the relative stereochemistry.

A new lariciresinol-type butyrolactone lignan derived from hydroxymatairesinol and its identification in spruce wood.

When the natural lignan hydroxymatairesinol (1) was treated with an alkaline aqueous solution, it partially rearranged to isomeric forms of a lariciresinol-type butyrolactone lignan. The two major diastereomers formed (2 and 3) were isolated by column and medium-pressure chromatography, and their structures were elucidated by MS and NMR techniques. These previously unknown butyrolactone lignans were identified as naturally occurring in spruce knotwood by GC, GC-MS, and HPLC-ESI MS/MS analyses. The formation of isohydroxymatairesinol (2) and epi-isohydroxymatairesinol (3) from hydroxymatairesinol (1), and their detection in rat urine after administration of 1, is discussed.

Reactions of the natural lignan hydroxymatairesinol in basic and acidic nucleophilic media: formation and reactivity of a quinone methide intermediate.

The chemical properties and synthetic modifications of the natural lignan hydroxymatairesinol in basic and acidic nucleophilic media were studied. Hydroxymatairesinol presumably reacts via a quinone methide and a carbonium ion mechanism under basic and acidic conditions, respectively. In these conditions the benzylic hydroxyl group was displaced by nucleophiles yielding new 7-substituted butyrolactone lignans. Reactions in alcoholic basic solutions yielded the 7-alkoxy ethers diastereoselectively. Several previously known lignans as well as new lignans and lignan derivatives were synthesised. The transformations were monitored and the products identified by HPLC-MS and NMR.

New chemo and chemo-enzymatic synthesis of β-benzyl-γ-butyrolactones

β-Benzyl-γ-butyrolactones, important intermediates for the synthesis of butyrolactone lignans, have been synthesized by a new route involving preparation of α-β-unsaturated formyl esters. The formyl esters can easily be converted into the desired butyrolactones either through chemical transformations or by enzymatic methods.

Immunomodulatory effect of arctigenin, a lignan compound, on tumour necrosis factor-alpha and nitric oxide production, and lymphocyte proliferation.

We have investigated the immunomodulatory effects of arctigenin, a dibenzyl butyrolactone lignan compound, on tumour necrosis factor (TNF)-alpha and nitric oxide (NO) production, and lymphocyte proliferation. Arctigenin inhibited strongly TNF-alpha production by lipopolysaccharide-stimulated murine macrophage RAW264.7 and differentiated human macrophage U937 with IC50 values of 5.0 and 3.9 microM, respectively, without displaying cytotoxicity. The TNF-alpha inhibitory effect of arctigenin in lipopolysaccharide-triggered RAW264.7 cells was increased by co-treatment with several known TNF-alpha inhibitors. It also potently attenuated T and B cell proliferation stimulated by concanavalin A and lipopolysaccharide in a dose-dependent manner with IC50 values of 2.9 and 14.6 microM, respectively. In contrast, the compound showed a different pattern in lipopolysaccharide- and interferon (IFN)-gamma-induced NO production from RAW264.7 cells. Arctigenin inhibited NO release by IFN-gamma signal, whereas it significantly enhanced lipopolysaccharide-triggered NO production in RAW264.7 cells. The results suggested that arctigenin may regulate immune responses in activated macrophages and lymphocytes including TNF-alpha and NO production and lymphocyte proliferation.

The role of dianion coupling in the synthesis of dibenzylbutane lignans.

Dianion coupling reactions have been used to prepare structurally related lignan natural products in racemic form. A readily available alpha-idocarboxylic acid 10 has been employed in separate sequences to afford the tetrahydrofuran lignan burseran [6] and the butyrolactone lignan deoxypodorhizon [7]. The key strategy for both burseran and deoxypodorhizon involved reaction of the appropriate dianion with an alpha-iodo carboxylate salt 13. Equilibration under acid or base was employed to create the trans stereochemistry of the substituted benzyl side chains of both burseran and deoxypodorhizon. To achieve proper dianion reactivity and to avoid side reactions in the synthetic sequence to deoxypodorhizon, it was necessary to develop the chemistry of acylsulfonamide dianions. As a further structure proof, our synthetic deoxypodorhizon was also utilized as a substrate in a successful sequence to isostegane [8], a known relay intermediate to the antineoplastic prototype steganacin [9].

A butyrolactone lignan disaccharide from Flacourtia ramontchi

beta-Sitosterol, beta-sitosterol-beta-D-glucopyranoside and a butyrolactone lignan disaccharide, ramontoside, were isolated from the heartwood of Flacourtia ramontchi. The structure of ramontoside was determined as diphyllin-4-O-[beta-D-glucopyranosyl(1---4)]-beta- 2,3-di-O-methyl-D-xylopyranoside by hydrolysis and spectral data.