Δ-lactone Ring Research Articles

Secotrijugins A−D, four highly oxidized and rearranged limonoids from Trichilia sinensis and their anti-inflammatory activity

Four undescribed highly oxidized and rearranged limonoids, secotrijugins A-D, were purified from the leaves and twigs of Trichilia sinensis. Within them, secotrijugin A was characterized as a rare 30-nortrijugin-type limonoid with an unusual cleavage of 1,14-ether bond, secotrijugins B and C represented new examples with the cleavage of δ-lactone ring D, and secotrijugin D was a rare trijugin-type limonoid with an unusual 2,6-oxygen bridge. The structures of limonoids were characterized by means of spectroscopic analysis and ECD calculations. The cellular screening revealed that secotrijugin B was the most active against LPS-stimulated NO production in BV-2 cells, which played an anti-inflammatory role by downregulating COX-2 and iNOS protein expression. The further in vivo experiments confirmed that secotrijugin B had strong in vivo anti-inflammatory effect via suppressing NO and ROS generation.

3,4-Seco-Isopimarane Diterpenes from the Twigs and Leaves of Isodon Flavidus.

Three isopimarane diterpenes [fladins B (1), C (2), and D (3)] were isolated from the twigs and leaves of Chinese folk medicine, Isodon flavidus. The chemical structures were determined by the analysis of the comprehensive spectroscopic data, and the absolute configuration was confirmed by X-ray crystallographic analysis. The structures of 1–3 were formed from isopimaranes through the rearrangement of ring A by the bond break at C-3 and C-4 to form a new δ-lactone ring system between C-3 and C-9. This structure type represents the first discovery of a natural isopimarane diterpene with an unusual lactone moiety at C-9 and C-10. In the crystal of 1, molecules are linked to each other by intermolecular O-H···O bonds, forming chains along the b axis. Compounds 1–3 were evaluated for their bioactivities against different diseases. None of these compounds displayed cytotoxic activities against HCT116 and A549 cancer cell lines, antifungal activities against Trichophyton rubrum and T. mentagrophytes, or antiviral activities against HIV entry at 20 µg/mL (62.9–66.7) µM. Compounds 1 and 3 did not show antiviral activities against Ebola entry at 20 µg/mL either; only 2 was found to show an 81% inhibitory effect against Ebola entry activity at 20 µg/mL (66.7 µM). The bioactivity evidence suggested that this type of compound could be a valuable antiviral lead for further structure modification to improve the antiviral potential.

Chemoenzymatic synthesis, computational investigation, and antitumor activity of monocyclic lankacidin derivatives

We investigated the importance of the δ-lactone ring (C1–C5) in lankacidin C using chemoenzymatic synthesis and computational prediction and assessing biological activity, including antitumor activity. Pyrroloquinoline quinone-dependent dehydrogenase (Orf23) in Streptomyces rochei was used in the chemoenzymatic synthesis of lankacyclinone C, a novel lankacidin C congener lacking the δ-lactone moiety. Orf23 could convert the monocyclic lankacidinol derivatives, lankacyclinol and 2-epi-lankacyclinol, to the C-24 keto compounds, lankacyclinone C and 2-epi-lankacyclinone C, respectively, elucidating the relaxed substrate specificity of Orf23. Computational prediction using molecular dynamics simulations and the molecular mechanics/generalized Born-surface area protocol indicated that binding energy values of all the monocyclic derivatives are very close to those of lankacidin C, which may reflect a comparable affinity to tubulin. Monocyclic lankacidin derivatives showed moderate antitumor activity when compared with bicyclic lankacidins, suggesting that the δ-lactone moiety is less important for antitumor activity in lankacidin-group antibiotics.

Caesalpinaxin, a cassane-type diterpenoid with a 21-carbon core skeleton from the seeds of Caesalpinia minax possessing pro-angiogenetic property

A novel cassane-type diterpenoid, caesalpinaxin (1), was isolated from the seeds of Caesalpinia minax Hance. The structure of caesalpinaxin was established by means of spectroscopic techniques (NMR, HR-ESIMS, UV and IR). The absolute configuration of caesalpinaxin was determined by quantum chemical calculations of its theoretical electronic circular dichroism (ECD) spectrum. Caesalpinaxin is the first cassane-type diterpenoid with 21 carbons core skeleton, containing an unusual δ-lactone ring. A plausible biosynthetic pathway was proposed for compound 1. Furthermore, caesalpinaxin was tested for the pro-angiogenetic activity on human umbilical vein endothelial cells(HUVECs). The results indicated that this compound significantly stimulated migration and tuber formation through enhancing the level of vascular endothelial growth factor (VEGF). Thus, caesalpinaxin might be applied in accelerating wound healing.

Structurally diverse limonoids and bio-active evaluation from Trichilia connaroides

Four new limonoids, named as trichiconlide G (1), 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), 21-oxo-23-hydroxyltrijugin F (4), along with sixteen known analogues (5–20) were isolated from the leaves and twigs of Trichilia connaroides. Their structures and absolute configurations were determined by spectroscopic analyses, X-ray diffraction analysis, and TD-DFT-ECD calculations. Trichiconlide G (1) is one rare naturally occurring 1,2-seco phragmalin-type limonoid bearing a C-7/28 δ-lactone ring. Additionally, 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), and 21-oxo-23-hydroxyltrijugin F (4) are three naturally occurring limonoids with a rare C-16/8 δ-lactone ring. All isolates were evaluated for their cytotoxic and anti-inflammatory activities. None of compounds exhibited cytotoxicity against five human cancer cell lines A-549, HepG2, 5-8F, Siha, and SCC-4 at the concentration of 40 μM. Compounds 16 and 17 showed moderate anti-inflammatory activity with IC50 values of 28.45 ± 2.51 and 22.66 ± 2.01 μM, respectively.

Tetranorlanostane and Lanostane Triterpenoids with Cytotoxic Activity from the Epidermis of Poria cocos.

Two unprecedented tetranorlanostane triterpenoids, poricolides A (1) and B (2), and two new lanostane triterpenoids, 3β-acetoxy-24-methyllanosta-8,16,24(31)-trien-21-oic acid (3) and 3β-acetoxylanosta-7,9(11),16,23-tetraen-21-oic acid (4), were isolated from the epidermis of Poria cocos. The structures of 1-4 were determined via analysis of 1 H-, 13 C-, and 2D-NMR, and HR-ESI-MS data, and the absolute configurations of 1 and 3 were established by single-crystal X-ray diffraction analysis. Compounds 1 and 2 were the first report of tetranorlanostane triterpenoid having a δ-lactone ring at C(17). Compounds 3 and 4 were rare lanostane triterpenoids having a double bond between C(16) and C(17). Compounds 1-4 exhibited potent antiproliferative effects against A549, SMMC-7721, MCF-7, and SW480 cancer cell lines with IC50 values from 16.19±0.38 to 27.74±1.12 μM.

LC-ESI-FT-MSn Metabolite Profiling of Symphytum officinale L. Roots Leads to Isolation of Comfreyn A, an Unusual Arylnaphthalene Lignan.

Preparations of comfrey (Symphytum officinale L.) roots are used topically to reduce inflammation. Comfrey anti-inflammatory and analgesic properties have been proven in clinical studies. However, the bioactive compounds associated with these therapeutic activities are yet to be identified. An LC–ESI–Orbitrap–MSn metabolite profile of a hydroalcoholic extract of comfrey root guided the identification of 20 compounds, including a new arylnaphthalene lignan bearing a rare δ-lactone ring, named comfreyn A. Its structure was determined using extensive 2D NMR and ESI–MS experiments. Additionally, the occurrence of malaxinic acid, caffeic acid ethyl ester, along with the lignans ternifoliuslignan D, 3-carboxy-6,7-dihydroxy-1-(3′,4′-dihydroxyphenyl) -naphthalene, globoidnan A and B, and rabdosiin was reported in S. officinale for the first time. These results helped to redefine the metabolite profile of this medicinal plant. Finally, caffeic acid ethyl ester and comfreyn A were found to significantly inhibit E-selectin expression in IL-1β stimulated human umbilical vein endothelial cells (HUVEC), with EC values of 64 and 50 µM, respectively.

Synthesis of enantiomerically pure oxygen-containing helical heterocycles via stereospecific rearrangement of benzofused-2,2′-diphenoquinone derivatives

Three different enantiomerically pure poly-condensed oxygen-containing heterocyclic compounds were synthesized by the rearrangement of enantiomerically pure (P)- and (M)-benzofused-2,2′-diphenoquinones. The three products were: a spiro compound bearing a γ-lactone ring, and two derivatives with a helical structure, one containing a δ-lactone ring and the other oxepin and furan rings. When the helical quinone derivative was heated in solution, the rearrangement proceeded with retention of configuration. Thus, (P)-quinone derivatives gave the corresponding (S)-spiro and (P)-helicene-like derivatives without compromising their enantiomeric purity, and vice versa.

Four new ergostane-type steroids from Lasiodiplodia pseudotheobromae

Four new ergostane-type steroids (1–4) were isolated from the fungus of Lasiodiplodia pseudotheobromae. Their structures were elucidated based on spectroscopic methods and single crystal X-ray diffraction analysis. Compound 1, an unusual steroid, possesses a unique ring system with A-ring contracted and formed a new δ-lactone ring between C-3 and C-9. The absolute configurations of compound 1 was determined by ECD calculation while compound 2 was confirmed by single-crystal X-ray diffraction analysis.

Carapanins A-C: new limonoids from andiroba (Carapa guianensis) fruit oil.

Carapanins A-C (1-3) were isolated from the fruit oil of Carapa guianensis. Compounds 1 and 2 are limonoids with unique structures. Namely, compound 1 is an andirobin-type limonoid with a C-15/C-30 γ-lactone instead of the δ-lactone of the D-ring, and compound 2 is a mexicanolide-type limonoid with a C-16/C-30 δ-lactone ring. The absolute structures of 1 and 2 were determined using X-ray crystallography, whereas the structure of 3 was established mainly via NMR and mass spectroscopy. The inhibitory effects of 1-3 on nitric oxide production were evaluated, and it was revealed that 2 and 3 were potent nitric oxide inhibitors.

Synthesis of Nonano-9-lactone Fused to a δ-Lactone Ring

With the goal of obtaining fused dilactones, the carbohydrate moiety of diastereoisomeric Michael adducts of levoglucosenone and cyclohexanone was converted to δ-lactone and its derivatives fused to an octahydrochromene fragment. The subsequent oxidative cleavage of the C-C bridge in the latter by the action of pyridiniun chlorochromate (PCC) afforded nonano-9-lactone fused at the C6-C7 bond to δ-lactone or methyl-δ-lactol. The presence of a carbonyl group in the carbohydrate moiety was found to prevent C-C bond cleavage.

Trichiconlides C[sbnd]F, four new limonoids with 1,2-seco phragmalin-type carbon skeleton from the fruits of Trichilia connaroides

Phytochemical investigation of the fruits from Trichilia connaroides led to the isolation of four rare 1,2-seco phragmalin-type limonoids (1–4) with C-7/28 δ-lactone ring along with two known triterpenoids (5–6). An oxygen bridge between C-1 and C-2 formed an rare 9-oxa-tricyclo[3.3.2.17,10]undecane-2-ene moiety in structure of 1 and 2, and 3–4 possessed a bicyclo[5.2.14,10]decane skeleton. Their structures were established based on extensive spectroscopic methods and their absolute configurations of 1 were confirmed by TDDFT/ECD calculation and comparative analysis. Compounds 5–6 showed moderate inhibitory effects on Hela tumor cell lines with inhibition ratio values of 83.8% and 87.1% at concentration 40μM, respectively.

Organocatalytic Doubly Annulative Approach to 3,4-Dihydrocoumarins Bearing a Fused Pyrrolidine Scaffold.

A new strategy for the highly enantio- and diastereoselective synthesis of 3,4-dihydrocoumarin derivatives bearing a fused pyrrolidine ring is reported. It is based on a Brønsted base catalyzed cascade reactivity between β,γ-unsaturated-α-ketophosphonates and imines (derived from various salicylaldehydes and diethyl aminomalonate). The approach can be described as a doubly annulative strategy where both the pyrrolidine moiety and the δ-lactone ring of the 3,4-dihydrocoumarin framework are constructed starting from acyclic precursors.

Phytochemistry and biosynthesis of δ-lactone withanolides

Withanolides are highly oxygenated natural products. These C28 steroids with ergostane-based skeletons functionalized at C-22 and C-26 form six-membered δ-lactone rings. Withanolides containing a δ-lactone side chain often occur in Solanaceae and have a variety of biological activities because of their complicated structures. Characteristic spectroscopic behaviors and biosynthesis of withanolides are conducive to their structural elucidation and “biomimetic synthesis”, respectively. However, the last review to summarize their spectroscopic features and biosynthesis was in 1996. Since then, many withanolides with novel structures have been described by their spectra with biosynthesis investigated with many bioassays. This review surveys δ-lactone withanolides and emphasizes their spectral features, configurations and biosynthetic genes. The period reviewed includes through January 2014. We also include phytochemical species.

Chrodrimanins I and J from the Antarctic Moss-Derived Fungus Penicillium funiculosum GWT2-24.

Two new meroterpenoids, named chrodrimanins I and J (1 and 2), together with five known biosynthetically related chrodrimanins (3-7), were isolated from the culture of the Antarctic moss-derived fungus Penicillium funiculosum GWT2-24. Distinguished from all of the reported chrodrimanins, compounds 1 and 2 possess a unique cyclohexanone (E ring) instead of a δ-lactone ring. These structures including the absolute configurations were established on the basis of MS, NMR, and X-ray crystallographic analysis. Compounds 1-7 showed no cytotoxic or antibacterial activities, while the known compounds 3, 5, and 6 exhibited inhibitory activities against influenza virus A (H1N1), with IC50 values ranged from 21 to 57 μM.

Phragmalin-type limonoids with NF-κB inhibition from Chukrasia tabularis var. velutina

Chemical investigation on Chukrasia tabularis var. velutina led to the identification of eight new phragmalin-type limonoids (1–8), as well as 20 known analogues. Compounds 1–4 are a rare class of C-15-acyl phragmalin-type limonoids, and particularly compounds 2–4 also possess a δ-lactone ring formed between C-16 and C-30. All the isolates were evaluated for inhibitory effects on NF-κB production, and four of which showed significant inhibitions.

6α,7α-Epoxy-5α-hydroxy-1-oxo-22R-witha-2,24-dienolide(withanolide B), 5β,6β-Epoxy-4β,20-dihydroxy-1-oxo-22R-witha-2,24-dienolide(withanolide D), and 4β,27-Dihydroxy-1-oxo-22R-witha-2,5,24-trienolide(5,6-deoxywithaferin A) in Roots of Withania somnifera: Isolation and Their Crystal Structures

6α,7α-Epoxy-5α-hydroxy-1-oxo-22R-witha-2,24-dienolide (C28H38O5), 5β,6β-epoxy-4β,20-dihydroxy-1-oxo-22R-witha-2,24-dienolide (C28H38O6), and 4β,27-dihydroxy-1-oxo-22R-witha-2,5,24-trienolide (C28H38O5), were isolated from Withania somnifera roots. The structures of these withanolides were established by spectroscopic analysis and X-ray diffraction studies as withanolide B, withanolide D, and 5,6-deoxywithaferin A, respectively. All three compounds crystallize in the orthorhombic space group P212121 with unit cell parameters: a = 9.1012(3) A, b = 12.2728(4) A, c = 21.5396(7) A, Z = 4 for withanolide B; a = 7.6569(5) A, b = 9.9426(7) A, c = 33.767(2) A, Z = 4 for withanolide D; and a = 6.9310(3) A, b = 10.6745 (4) A, c = 34.667(2) A, Z = 4 for 5,6-deoxywithaferin A, respectively. The crystal structures have been solved by direct methods and refined to R 1 = 0.024 for 4,290 unique reflections (withanolide B), R 1 = 0.042 for 4,601 unique reflections (withanolide D), and R 1 = 0.033 for 4,626 unique reflections (5,6-deoxywithaferin A), respectively. Rings B, C, D of the steroid skeletons are trans connected while ring C adopts a chair conformation, five-membered ring D adopts a half-chair, and the δ-lactone ring E in the side chain adopts a sofa conformation. For withanolide B, rings A and B are trans connected and both rings A and B exist in a half-chair conformation; for withanolide D, rings A and B are cis connected, and ring A has a sofa conformation while ring B has a distorted boat conformation; for 5,6-deoxywithaferin A, ring A has a half chair conformation and ring B exists as a boat conformation. The crystal structures of 6α,7α-epoxy-5α-hydroxy-1-oxo-22R-witha-2,24-dienolide (withanolide B), 5β,6β-epoxy-4β,20-dihydroxy-1-oxo-22R-witha-2,24-dienolide (withanolide D), and 4β,27-dihydroxy-1-oxo-22R-witha-2,5,24-trienolide (5,6-deoxywithaferin A) are described.

Regiospecific 6-Endo-Annulation of in Situ Generated 3,4-Dienamides/Acids: Synthesis of δ-Lactams and δ-Lactones

A novel and efficient method for the construction of α-(1,3-dithiolan-2-ylidene) δ-lactam and δ-lactone rings has been developed. It involves the regiospecific 6-endo-annulation of in situ generated 2-(1,3-dithiolan-2-ylidene)-3,4-dienamides/acids from the dehydrative coupling of α-oxo ketene dithioacetals with tertiary propargyl alcohols promoted by BF3·Et2O. A range of α-(1,3-dithiolan-2-ylidene) δ-lactams and δ-lactones are obtained in good to high yields. In addition, indenes are prepared by using α-acetyl ketene dithioacetal as the precursor.

Segunoside: a new iridolactone-β-glucoside from the stem bark of Hunteria umbellata (K. Schum)

Abstract The present conjectural chemical nature of the antidiabetic principles of the tropical plant Hunteria umbellata prompted chemical investigations into an aqueous fraction of a methanolic crude extract of the stem bark of the plant, leading to the isolation of a new iridolactone-β-glucoside, segunoside. Isolated by prep. HPLC and characterized largely by 2D NMR techniques, segunoside features a unique fusion of a δ-lactone ring to an unsaturated cyclopentano[c]tetrahydropyran ring system typical of iridoids to become the first reported iridoid for the plant. The possible contribution of this and other simple β-glycosides to the antidiabetic properties of H. umbellata is conjectured on chiral recognition grounds.

Interaction of Digitalis-Like Compounds with P-Glycoprotein

Digitalis-like compounds (DLCs), or cardiac glycosides, are produced and sequestered by certain plants and animals as a protective mechanism against herbivores or predators. Currently, the DLCs digoxin and digitoxin are used in the treatment of cardiac congestion and some types of cardiac arrhythmia, despite a very narrow therapeutic index. P-glycoprotein (P-gp; ABCB1) is the only known ATP-dependent efflux transporter that handles digoxin as a substrate. Ten alanine mutants of human P-gp drug-binding amino acids-Leu(65), Ile(306), Phe(336), Ile(340), Phe(343), Phe(728), Phe(942), Thr(945), Leu(975), and Val(982)-were generated and expressed in HEK293 cells with a mammalian baculovirus system. The uptake of [(3)H]-N-methyl-quinidine (NMQ), the P-gp substrate in vesicular transport assays, was determined. The mutations I306A, F343A, F728A, T945A, and L975A abolished NMQ transport activity of P-gp. For the other mutants, the apparent affinities for six DLCs (cymarin, digitoxin, digoxin, peruvoside, proscillaridin A, and strophanthidol) were determined. The affinities of digoxin, proscillaridin A, peruvoside, and cymarin for mutants F336A and I340A were decreased two- to fourfold compared with wild type, whereas that of digitoxin and strophanthidol did not change. In addition, the presence of a hydroxyl group at position 12β seems to reduce the apparent affinity when the side chain of Phe(336) and Phe(942) is absent. Our results showed that a δ-lactone ring and a sugar moiety at 3β of the steroid body are favorable for DLC binding to P-gp. Moreover, DLC inhibition is increased by hydroxyl groups at positions 5β and 19, whereas inhibition is decreased by those at positions 1β, 11α, 12β, and 16β. The understanding of the P-gp-DLC interaction improves our insight into DLCs toxicity and might enhance the replacement of digoxin with other DLCs that have less adverse drug effects.