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Eleven withanolides including six previously undescribed compounds, 16β-hydroxyixocarpanolide, 24,25-dihydroexodeconolide C, 16,17-dehydro-24-epi-dioscorolide A, 17-epi-philadelphicalactone A, 16-deoxyphiladelphicalactone C, and 4-deoxyixocarpalactone A were isolated from aeroponically grown Physalis philadelphica. Structures of these withanolides were elucidated by the analysis of their spectroscopic (HRMS, 1D and 2D NMR, ECD) data and comparison with published data for related withanolides. Cytotoxic activity of all isolated compounds was evaluated against a panel of five human tumor cell lines (LNCaP, ACHN, UO-31, M14 and SK-MEL-28), and normal (HFF) cells. Of these, 17-epi-philadelphicalactone A, withaphysacarpin, philadelphicalactone C, and ixocarpalactone A exhibited cytotoxicity against ACHN, UO-31, M14 and SK-MEL-28, but showed no toxicity to HFF cells.

The proteases TMPRSS2 (transmembrane protease serine 2) and furin are known to play important roles in viral infectivity including systematic COVID-19 infection through priming of the spike protein of SARS-CoV-2 and related viruses. To discover small-molecules capable of inhibiting these host proteases, we established convenient and cost-effective cell-based assays employing Vero cells overexpressing TMPRSS2 and furin. A cell-based proteolytic assay for broad-spectrum protease inhibitors was also established using human prostate cancer cell line LNCaP. Evaluation of camostat, nafamostat, and gabexate in these cell-based assays confirmed their known TMPRSS2 inhibitory activities. Diminazene, a veterinary medicinal agent and a known furin inhibitor was found to inhibit both TMPRSS2 and furin with IC

Made available in DSpace on 2021-06-25T11:23:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-10-23 National Institutes of Health Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) College of Agriculture & Life Sciences of the University of Arizona Center for Scientific Computing (NCC/GridUNESP) of Sa eo Paulo State University (UNESP) Incorporation of the epigenetic modifier suberoylanilide hydroxamic acid (SAHA) into a potato dextrose broth culture of the endophytic fungus Aspergillus sp. AST0006 affected its polyketide biosynthetic pathway providing two new 3-(4-oxopyrano)-chromen-2-ones, aspyranochromenones A (1) and B (2), and the isocoumarin, (-)-6,7-dihydroxymellein (3). Eight additional metabolites (4-11) and two biotransformation products of SAHA (12-13) were also encountered. The planar structures and relative configurations of the new metabolites 1-2 were elucidated with the help of high-resolution mass, 1D and 2D NMR spectroscopic data and the absolute configurations of 1-3 were determined by comparison of experimental and calculated ECD data. Possible biosynthetic pathways to 1 and 2 are presented. (C) 2020 Elsevier Ltd. All rights reserved. Univ Arizona, Coll Agr & Life Sci, Southwest Ctr Nat Prod Res, Sch Nat Resources & Environm, 250 E Valencia Rd, Tucson, AZ 85706 USA Sao Paulo State Univ, Inst Chem, BR-14800900 Araraquara, SP, Brazil Jiangsu Normal Univ, Key Lab Biotechnol Med Plants Jiangsu Prov, 101 Shanghai Rd, Xuzhou 221116, Jiangsu, Peoples R China Univ Arizona, Coll Agr & Life Sci, Sch Plant Sci, Tucson, AZ 85721 USA Fluminense Fed Univ, Chem Inst, Dept Organ Chem, BR-24020141 Niteroi, RJ, Brazil Univ Fed Sao Paulo, Inst Sci & Technol, BR-12231280 Sao Jose Dos Campos, SP, Brazil Sao Paulo State Univ, Inst Chem, BR-14800900 Araraquara, SP, Brazil National Institutes of Health: R01 CA90265 National Institutes of Health: P41 GM094060 FAPESP: 2018/05905-5 FAPESP: 2014/25222-9

The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this represents the first detailed structure activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.

Oxygenated guaiane-type sesquiterpenes, xylaguaianols A–D (1–4), an iso-cadinane-type sesquiterpene isocadinanol A (5), and an α-pyrone 9-hydroxyxylarone (6), together with five known sesquiterpenes (7–11), and four known cytochalasins (12–15) were isolated from a culture broth of Xylaria sp. NC1214, a fungal endophyte of the moss Hypnum sp. The structures of all compounds were elucidated by the analysis of their spectroscopic data and relative configurations of 1–5 were determined with the help of NMR NOESY experiments. Cytochalasins C (12), D (13), and Q (14) were investigated for their cytotoxic activity against five tumor cell lines. Cytochalasin D showed significant cytotoxicity against all five cell lines, with IC50s ranging from 0.22 to 1.44 μM, whereas cytochalasins C and Q exhibited moderate, but selective cytotoxicity.

Summary The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this is the first detailed structure-activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.

In an attempt to maximize production and the structural diversity of plant metabolites, the effect of growing the medicinal plant Withania somnifera under soil-less aeroponic conditions on its ability to produce withaferin A and withanolides was investigated. It resulted in the isolation and characterization of two compounds, 3α-(uracil-1-yl)-2,3-dihydrowithaferin A (1) and 3β-(adenin-9-yl)-2,3-dihydrowithaferin A (2), in addition to 10 known withanolides including 2,3-dihydrowithaferin A-3β-O-sulfate. 3β-O-Butyl-2,3-dihydrowithaferin A (3), presumably an artifact formed from withaferin A during the isolation process was also encountered. Reaction of withaferin A with uracil afforded 1 and its epimer, 3β-(uracil-1-yl)-2,3-dihydrowithaferin A (4). The structures of these compounds were elucidated on the basis of their high resolution mass and NMR spectroscopic data.

Syntheses of the bacterial surfactants 6S,6S-, 9S,9S-, and 9U,9U-flavolipids confirmed the structures proposed for them from spectroscopic analysis of a flavolipid mixture and made pure flavolipids available for the first time. All three synthetic flavolipids and a straight chain analogue were found to be weakly cytotoxic and to inhibit metastatic cancer cell migration, with 9U,9U-flavolipid (the most abundant natural flavolipid) having the most activity. Biosynthetic routes to the branched side-chains of the flavolipids are suggested, and it is proposed that branched chains are employed to hinder biodegradation.

Preparations of the roots of the medicinal plant Withania somnifera (L.) Dunal commonly called ashwagandha have been used for millennia in the Ayurvedic medical tradition of India as a general tonic to relieve stress and enhance health, especially in the elderly. In modern times, ashwagandha has been shown to possess intriguing antiangiogenic and anticancer activity, largely attributable to the presence of the steroidal lactone withaferin A as the major constituent. When cultured using the aeroponic technique, however, this plant was found to produce a new natural product, 2,3-dihydrowithaferin A-3beta-O-sulfate (1), as the predominant constituent of methanolic extracts prepared from aerial tissues. The characteristic bioactivities exhibited by 1 including inhibition of cancer cell proliferation/survival, disruption of cytoskeletal organization and induction of the cellular heat-shock response paralleled those displayed by withaferin A (2). The delayed onset of action and reduced potency of 1 in cell culture along with previous observations demonstrating the requirement of the 2(3)-double bond in withanolides for bioactivity suggested that 1 might be converted to 2 in cell culture media and this was confirmed by HPLC analysis. The abundant yield of 1 from aeroponically cultivated plants, its good aqueous solubility and spontaneous conversion to 2 under cell culture conditions, suggest that 1 could prove useful as a readily formulated prodrug of withaferin A that merits further evaluation in animal models.

Reaction of pristimerin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in a biomimetic-type coupling leading to xuxuarines Eα and Eβ and not the previously reported Rzedowskia bistriterpenoids I and II suggesting that the structures proposed for these natural products need revision. A product obtained in this reaction by an unusual Diels-Alder addition followed by retro -Diels-Alder-type elimination was characterized as pristimerin dicyanophenalenedione. Complete 1 H, and 13 C NMR spectral assignments of xuxuarines Eα and Eβ have been made by the application of 1D and 2D NMR techniques.

Bioactivity-guided fractionation of a cytotoxic extract of Aspergillus tubingensis, a fungal strain occurring in the rhizosphere of the Sonoran desert plant, Fallugia paradoxa, afforded a dimeric naphtho-gamma-pyrone asperpyrone D, nine known naphtho-gamma-pyrones, funalenone, and the cytotoxic cyclic penta-peptide, malformin A1.

Synthesis of the β-carotene oxidation product, 2,3-dihydro-5,8-endoperoxy-β- apo -carotene-13-one ( 1 ) was achieved in six steps starting from β-ionone. Photo-oxygenation of all trans -retinoic acid ( 8 ) and 13- cis -retinoic acid ( 9 ) produced a mixture of 5 S *,8 S *-epidioxy-5,8-dihydroretinoic acid ( 10 ) and 13- cis -5 S *,8 S *-epidioxy-5,8-dihydroretinoic acid ( 11 ). Methylation of the crude photo-oxygenation mixture afforded the corresponding methyl esters 12 and 13 , respectively, both of which underwent ready aerial oxidation yielding hitherto unknown oxidation products of retinoic acid identified as methyl 5 S *,8 S *-epidioxy-9,10β-epoxy-5,8,9,10-tetrahydroretinoate ( 14 ) and methyl 13- cis -5 S *,8 S *-epidioxy-9,10β-epoxy-5,8,9,10-tetrahydroretinoate ( 15 ). Evaluation of 1 , all trans -retinoic acid ( 8 ), 13- cis -retinoic acid ( 9 ), and the photo-oxygenation products 10 – 15 in a panel of five cancer cell lines showed 1 to be inactive and that 11 is significantly cytotoxic compared with the other retinoic acid analogs suggesting the requirement of the carboxylic acid moiety and the cis -geometry of the 13(14) double bond for cytotoxic activity.

Five new isocoumarins, paraphaeosphaerins A–C and chaetochiversins A and B, biogenetically related to monocillin I and radicicol, have been isolated from solid agar cultures of Paraphaeosphaeria quadriseptata and Chaetomium chiversii, two fungal strains living in association with the Sonoran desert plants, Opuntia leptocaulis and Ephedra fasciculata, respectively. A new chroman-4-one, aposphaerin C, was also isolated from P. quadriseptata. Their structures and stereochemistry were elucidated using a combination of 1H and 13C homo- and hetero-nuclear 2D NMR techniques, 1H NMR analysis of Mosher's esters, and chemical correlations.

Ponicidin and oridonin are novel diterpenoids isolated from Rabdosia rubescens. We tested their effects in MCF-7 and MDA-MB-231 cells, as representing low and high invasive breast carcinoma, with normal MCF-10A cells. Clonogenicity and proliferation in MCF-7 cells were inhibited more significantly by ponicidin than oridonin, while the reverse was observed in MCF-10A cells. Ponicidin and oridonin induced S/G2M arrest and G1/S block in MCF-7 cells. In MCF-10A cells treated with either diterpenoid, induction of apoptosis was observed. Moreover, oridonin almost completely blocked MCF-10A progression from S to G2/M phase; in contrast, ponicidin-treated MCF-10A cells showed no discernable changes in cell cycle phase distribution. Neither diterpenoid affected growth of MDA-MB-231 cells, at the dose range effective for MCF-7 or MCF-10A cells. Ponicidin-treated MCF-7 cells expressed reduced levels of cyclin B1, cdc2, transcription factor E2F, and Rb including phosphorylation at S780. Less pronounced effects were found in cells treated with oridonin. Neither compound altered cyclin D1 and cdk4 in MCF-7 cells. In MCF-10A cells, oridonin was more active than ponicidin in inhibiting the expression of cyclin B1, cdc2, S780-phosphorylated Rb, and E2F. To further investigate induction of apoptosis in MCF-10A cells, we measured changes in NF-kappaB. Decreases in p65 or p50 forms of NF-kappaB and its upstream regulator I-kappaB were found in oridonin-treated MCF-10A and not MCF-7 cells. Taken together, these results provide a mechanistic framework for the cellular effects of ponicidin and oridonin in different stage breast cancer cells.

Biomimetic-type reactions of the tricyclic pyridone alkaloid, (−)-fusoxypyridone [(−)-4,6′-anhydrooxysporidinone] (1), recently encountered in an endophytic strain of Fusarium oxysporum, and (−)-oxysporidinone (2) afforded (−)-sambutoxin (3) and an analogue of 1, identified as (−)-1’(6’)-dehydro-4,6′-anhydrooxysporidinone (4), thus confirming the structure previously proposed for 1 and suggesting that 1 – 3 bear the same relative stereochemistry. Oxidation of 4 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) yielded a hitherto unknown sambutoxin analogue, (−)-4,2′-anhydrosambutoxin (5).

2-Deacetoxytaxinine B, a taxane diterpenoid, was isolated from the stem bark of Taxus chinensis along with six known taxane diterpenoids and the diterpenolignan, brevitaxin. The structure of 2-deacetoxytaxinine was determined with the aid of spectroscopic techniques, including 2D NMR spectroscopy.

The leaves of Tocoyena formosa afforded two antifungal iridoids, α- and β-gardiol, and the new iridoids, mollugoside methyl ester and formosinoside. Formosinoside was characterized as its hexaacetyl derivative.

A new 4,5-dioxoaporphine alkaloid, 8-methoxyouregidione, along with artabotrine, ouregidione, liriodenine, oxocrebanine, oxobuxifoline, atherospermidine and lanuginosine have been isolated from Artabotrys zeylanicus . Investigation of Xylopia championii afforded O -methylmoschatoline and dicentrinone.

Phytochemical investigation of the outer root bark of Salacia reticulata var. β-diandra (Celastraceae) has resulted in the isolation of two novel quinonemethide triterpenoids (celastroloids), isoiguesterinol and 30-hydroxypristimerin, along with salacenonal, several known celastroloids and friedo-oleanane triterpenoids. Details of the structural elucidation and 1 H and 13 C NMR spectral assignments of these compounds are presented and their biogenetic significance is discussed.

Four new piperidine alkaloids, leptophyllin A (4), 3-acetylleptophyllin A (5), leptophyllin B (8), and (−)-spectaline (1), and 3 known piperidine alkaloids, (−)-spectalinine (2), canavaline (3), and iso-6-canavaline (7), were isolated by a bioassay-guided fractionation of a leaf extract of Cassia leptophylla. The alkaloids 1–3 were active in a mechanism-based DNA-modifying yeast assay and 2 was moderately active in Vero monkey and Chinese hamster ovary cell cytotoxicity assays.

Phytochemical investigation of Xylopia aethiopica (Annonaceae) has resulted in the isolation of two novel diterpenes, 15-oxo-(-)-trachyloban-19-oic acid and (-)-kaur-15-en-17-al-19-oic acid. Also encountered were the known compounds 15-hydroxy-(-)-trachyloban-19-oic acid, 15β-hydroxy-(-)-kaur-16-en-19-oic acid (as an inseperable mixture), 15-oxo-(-)-kaur-16-en-19-oic acid and sitosterol glucoside. 13C NMR assignments of 15-hydroxy-(-)- trachyloban-19-oic acid and the assignment of the configuration of its hydroxyl group at C-15 have been carried out for the first time.

Two new cytotoxic cytochalasins were isolated by brine shrimp bioassay-guided fractionation from a culture of the wood inhabiting fungus, Xylaria obovata . Their structures were determined as 19,20-epoxycytochalasin Q ( 1 ) and its deacetyl analog 2 by the application of spectroscopic techniques and chemical correlation with cytochalasin R. Acetylation of 2 yielded 1 . Both 1 and 2 were cytotoxic but were found to be inactive in an HIV-protease inhibitory assay and a mechanism-based DNA damaging yeast assay.

Bioassay-directed fractionation of the methyl ethyl ketone extract of Crescentia cujete yielded the naphthoquinones 1 and 2. Both compounds are cytotoxic, and 1 shows selective DNA-damaging activity against yeast. Detailed spectroscopic interpretation led to the assignment of the structures of 1 and 2 as 3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione and 9-hydroxy-3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione, respectively. This is the first report of this fused furofuran ring system, either as a natural product or a synthetic substance.

The 1 H and 13 C NMR spectra of three natural 14(15)-ene-quinonemethide nortriterpenoids, balaenonol, balaenol and isobalaendiol have been comple

The root bark of Pleiospermium alatum afforded five alkaloids, five coumarins, lupeol and stigmasterol. One of the acridones, 1,5,6-trihydroxy-2,3-dimethoxy-10-methyl-9-acridone is a new compound while another, 1-hydroxy-2,3,5,6-tetramethoxy-10-methyl-9-acridone, is a new natural product. Chemotaxonomic aspects of the occurrence of acridone and coumarins in Pleiospermium is discussed. Seselin, one of the coumarins encountered displayed significant antifungal activity against Cladosporium cladosporioides .

Quinone-methide and phenolic triterpenoids of the root outer bark of Celastrus paniculatus have been identified as celastrol, pristimerin, zeylasterone and zeylasteral whereas those of Kokoona reflexa root outer bark were pristimerin, zeylasterone and zeylasteral. Celastranhydride, an unusual triterpene anhydride isolated from K. zeylanica was shown to be present in K. reflexa, Cassine balae and Reissantia indica . Details of the isolation and structure elucidation of celastranhydride are presented along with the analysis of 1 H-detected heteronuclear multiple-bond multi-quantum correlation (HMBC) NMR spectrum which aided the confirmation of its structure. Extracts of C. balae, Gymnosporia emarginata, Pleurostylia opposita and R. indica were found to contain quinone-methides but were devoid of phenolic triterpenoids. The biosynthetic and chemotaxonomic significance of the co-occurrence of these triterpenoids in Celastraceae is discussed.

It is shown by spectroscopic methods and synthesis that the minor alkaloid C 10 H 8 N 2 O 2 from Broussonetia zeylanica is actually 8-hydroxyquinoline-4-carbaldehyde oxime and not 3,4′-dihydroxy-2,3′-bipyridine as was reported earlier.

Taxol ( 1 ) can be prepared in good yield by coupling the oxazoline carboxylic acid 5 with 7-(triethylsilyl)baccatin III, followed by hydrolysis. The oxazolines 7 and 8 can also be prepared directly from taxol.

The structure of celastranhydride, a novel triterpene anhydride isolated from Kokoona zeylanica and present in Cassine balae and Reissantia indica , all of the family Celastraceae, has been deduced as 1 from its spectral data including 2-D heteronuclear 1 H 13 C shift correlated NMR spectra.

Zeylasteral and desmethylzeylasterone, two new triterpenes from Kokoona zeylanica have been shown to be 2,3-dihydroxy-6,23-dioxo-24-nor-D:A-friedo-oleana-1,3,5(10),7-tetraen-29-oic acid methyl ester (20α) and 2,3-dihydroxy-6-oxo-24-nor-D:A-friedo-oleana-1,3,5(10),7-tetraen23,29-dioic acid (20α), respectively, and have been related to trimethylzeylasterone. A partial synthesis of trimethylzeylasterone starting from pristimerin has been achieved.

The methanolic extract of the fruits of Colocynthis vulgaris on acidic hydrolysis afforded in addition to cucurbitacin I and J a new cucurbitacin designated cucurbitacin T whose structure was elucidated as (24 S )-16,24-anhydro-25-methoxy-2,16α,20β,24-tetrahydroxy-3,11,22-trioxocucurbita-1,5-diene by spectroscopic methods. The biosynthetic significance of the co-occurrence of cucurbitacins I, J and T in C. vulgaris is discussed.

Zeylasterone, a new triterpene from Kokoona zeylanica, is shown to be 2,3-dihydroxy-6-oxo-24-nor-D:A-friedo-oleana-1,3,5(10),7-tetraen-23,29-dioic acid-29-methyl ester (20 α) (1), the first member of a new series of phenolic 24-nor-D:A-friedo-oleanans.

A new bark acid, isochapelieric acid (cis-chapelieric acid), chapelieric acid, friedelin, friedelan-3β-ol, canophyllal, canophyllol, friedelan-3β,28-diol, canophyllic acid and amentoflavone have been isolated and characterized from leaf extractives of Calophyllum calaba. 13CNMR spectra of methyl chapelierate and methyl isochapelierate have been recorded and interpreted. Leaf extractives of Garcinia spicata afforded an unidentified long chain carboxylic acid, friedelin, friedelan-3β-ol, sitosterol and the biflavanones GB-1, GB-1a, GB-2a and morelloflavone. Chemotaxonomic significance of the occurrence of some of the above foliar constituents in Calophyllum and Garcinia species is discussed.