Isoswinholide B and swinholide K,potently cytotoxic dimeric macrolides from Theonella swinhoei

Chemical investigation of an Indonesian specimen of Theonella swinhoei afforded the new dimeric macrolides isoswinholide B (5) and swinholide K (6), along with the known swinholides A (1), B (2) and D (3) and isoswinholide A (4). Isoswinholide B showed an unprecedented 21/19′ lactonization pattern, while swinholide K included an sp² methylene attached at C-4 and an additional oxymethine group at C-5, whose configuration has been determined through application of J-based configuration analysis. The isolated swinholides (1–6), with the exception of isoswinholide B, showed a cytotoxic activity on HepG2 (hepatocarcinoma cell line) in the nanomolar range.     

Oxirapentyns B–D produced by a marine sediment-derived fungus Isaria felina (DC.) Fr

Three new highly oxygenated chromene derivatives, oxirapentyns B–D (1–3) and one known oxirapentyn A (4) were isolated from the lipophilic extract of the marine-derived fungus Isaria felina KMM 4639. The structures of compounds 1–3 were determined based on spectroscopic methods. The absolute configuration of oxirapentyn B (1) as 2R, 4S, 5S, 6S, 7R, 8S, 9S was established by a combination of modified Mosher's method, X-ray analysis, and NOESY data. Oxirapentyn A (4) showed weak cytotoxicity against SK-Mel-5, SK-Mel-28 human malignant melanoma, and T-47D human breast cancer cell lines.     

Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques

We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis (FtFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC₅₀ of benzimidazole (?)-1 is ～100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (?)/(+)-1 and (?)/(+)-2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (?)-rotation for both compounds 1 and 2, while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for S-1 and S-2 than for their enantiomers, R-1 and R-2, consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (?) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (?) to (S)- and (+) to (R)- for compounds 1 and 2, and to further evaluate structural changes to improve efficacy.     

Heliotropiumides A and B,new phenolamides with N-carbamoyl putrescine moiety from Heliotropium foertherianum collected in Hawaii and their biological activities

Two new compounds heliotropiumides A (1) and B (2), phenolamides each with an uncommon carbamoyl putrescine moiety, were isolated from the seeds of a naturalized Hawaiian higher plant, Heliotropium foertherianum Diane & Hilger in the borage family, which is widely used for the treatment of ciguatera fish poisoning. The structures of compounds 1 and 2 were characterized based on MS spectroscopic and NMR analysis, and DP4+ calculations. The absolute configuration (AC) of compound 1 was determined by comparison of its optical rotation with those reported in literature. Compound 2 showed inhibition against NF-κB with an IC₅₀ value of 36 μM.     

Anti-inflammatory spiroaxane and drimane sesquiterpenoids from Talaromyces minioluteus (Penicillium minioluteum)

A new spiroaxane sesquiterpenoid talaminoid A (1) and two drimane sesquiterpenoid talaminoids B and C (2 and 3), together with four known compounds (4–7), were isolated from the solid culture broth of fungus Talaromyces minioluteum. The structures were determined by extensive 1D and 2D NMR and HRESIMS spectroscopic data analyses, and the absolute configuration of these new compounds were undoubtedly confirmed by X-ray crystal diffrations. Compound 1 is a rare spiroaxane sesquiterpenoid and the absolute configuration of spiroaxane sesquiterpenoid was determined for the first time. Compound 2 is the first drimane-type sesquiterpenoid containing both amino acid residue and butanediol group. Compounds 1, 4, and 5 showed significant suppressive effect on the production of NO on LPS induced BV-2 cells, with IC₅₀ values ranging from 4.97 to 7.81 μM. In addition, 1, 4, and 5 exhibited significant anti-inflammatory activities against the production of TNF-α and IL-6. Further immunofluorescence experiments revealed the mechanism of action to be inhibitory the NF- κB-activated pathway.     

Eudistomidin G,a new β-carboline alkaloid from the Okinawan marine tunicate Eudistoma glaucus and structure revision of eudistomidin B

A new β-carboline alkaloid, eudistomidin G (1), has been isolated from the Okinawan marine tunicate Eudistoma glaucus, and the structure was elucidated from spectroscopic data. Furthermore, the structure of eudistomidin B (2), which has been isolated from the same tunicate, was revised from 2a to 2b by detailed analyses of spectroscopic data. Asymmetric synthesis of the revised structure (2b) of eudistomidin B (2) and its (1S,10S)-diastereomer (2c) has been accomplished with the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configuration of eudistomidin B (2) was confirmed to be 2b possessing (1R,10S)-configuration, from comparison of the ¹H NMR data, CD spectra, [α]_D values, and HPLC analysis of 2b, 2c, and natural eudistomidin B.     

Penicillospirone from a marine isolate of Penicillium sp. (SF-5292) with anti-inflammatory activity

Chemical investigation of the EtOAc extract of a marine-derived fungal isolate Penicillium sp. SF-5292 yielded a new polyketide-type metabolite, penicillospirone (1). The structure of 1 was determined by analysis of spectroscopic data such as 1D and 2D NMR spectra and MS data, and the final structure including absolute configuration was unambiguously established by single-crystal X-ray diffraction analysis. In the evaluation of its anti-inflammatory effects, 1 inhibited the overproduction of nitric oxide (NO) and prostaglandin E₂ (PGE₂) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and BV2 microglia, and these inhibitory effects were correlated with the suppressive effect of 1 against overexpressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, 1 also inhibited the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-12. Overall, the anti-inflammatory effect of 1 was suggested to be mediated through the negative regulation of NF-κB pathway.     

Two new components from the rhizome of Anemarrhena asphodeloides Bge. and their antiplatelet aggregative activity

Two new components, anemarrhena A (1) and anemarrhena B (2), together with five known ones (3–7), were isolated from the rhizome of Anemarrhena asphodeloides Bge. Their structures were established by detailed spectral studies, including 1D-NMR (¹H NMR, ¹³C NMR and DEPT), 2D-NMR (HSQC, HMBC and NOESY), HR-ESI-MS and by the comparison with literature data. The absolute configuration of 2 was further determined by CD analysis. The isolated compounds were evaluated for their antiplatelet aggregative activity. Compounds 1, 2, 3, 5, 6 and 7 exhibited moderate activity of antiplatelet aggregation in vitro, compound 4 showed potential antiplatelet aggregation activity.     

Drechmerin H,a novel 1(2), 2(18)-diseco indole diterpenoid from the fungus Drechmeria sp. as a natural agonist of human pregnane X receptor

A novel 1(2), 2(18)-diseco indole diterpenoid, drechmerin H (1), was isolated from the fermentation broth of Drechmeria sp. together with a new indole diterpenoid, 2′-epi terpendole A (3), and a known analogue, terpendole A (2). Their structures were determined by HRESIMS, 1D and 2D NMR, ECD, and X-ray single crystal diffraction analyses as well as quantum chemical calculation. The abosulte configuration of terpendole A (2) was determined for the first time. Compound 1 displayed the significant agonistic effect on pregnane X receptor (PXR) with EC₅₀ value of 134.91 ± 2.01 nM, and its interaction with PXR was investigated by molecular docking. Meantime, a plausible biosynthetic pathway for compounds 1–3 is also discussed in the present work.     

Prenylated C6–C3 compounds from the roots of Illicium henryi

Eleven prenylated C₆–C₃ compounds, illihenryifunones A, B (1, 2), illihenryifunol A (3), illihenryipyranol A (4), illihenryiones A−G (5–11), and three known prenylated C₆–C₃ compounds (12–14), were isolated from the roots of Illicium henryi. Structures of 1–11 were elucidated by spectroscopic methods including NMR, HRESIMS, and CD. The absolute configuration of the 11,12-diol moiety in 5 was determined by observing its induced circular dichroism after addition of Mo₂(OAc)₄ in DMSO. The absolute configuration of C-11 in 4 was determined as S based on the Rh₂(OCOCF₃)₄-induced CD data; the absolute configuration of 3 was determined as R by comparison of its experimental and calculated electronic circular dichroism (ECD). The antioxidant activities of compounds 1–14 were also evaluated. Compound 4 exhibited strong antioxidant activity with an IC₅₀ value of 2.97 ± 1.30 μM, whereas compounds 3 and 8 showed antioxidant activities with IC₅₀ values of 44.36 ± 0.30 and 48.00 ± 2.01 μM, respectively.     

Heterocycles 32. Efficient kinetic resolution of 1-(2-arylthiazol-4-yl)ethanols and their acetates using lipase B from Candida antarctica

In this paper we describe the chemoenzymatic synthesis of new enantiomerically enriched (R)- and (S)-1-(2-arylthiazol-4-yl)ethanols and their acetates by enzymatic enantioselective acetylation of the racemic alcohols rac-2a–d and by methanolysis of the corresponding racemic esters rac-3a–d mediated by lipase B from Candida antarctica (CaL-B) in non-aqueous media. In terms of stereoselectivity and activity, both procedures, acylation and alcoholysis, gave similar good results (50% conversion, E ≫ 200). The absolute configuration of the kinetic resolution products was determined by a detailed ¹H NMR study of the Mosher's derivatives of (S)-2b.     

Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome

Via high-throughput screening of a natural compound library, we have identified a lipopeptide aldehyde, fellutamide B (1), as the most potent inhibitor of the Mycobacterium tuberculosis (Mtb) proteasome tested to date. Kinetic studies reveal that 1 inhibits both Mtb and human proteasomes in a time-dependent manner under steady-state condition. Remarkably, 1 inhibits the Mtb proteasome in a single-step binding mechanism with K_i = 6.8 nM, whereas it inhibits the human proteasome β5 active site following a two-step mechanism with K_i = 11.5 nM and  = 0.93 nM. Co-crystallization of 1 bound to the Mtb proteasome revealed a structural basis for the tight binding of 1 to the active sites of the Mtb proteasome. The hemiacetal group of 1 in the Mtb proteasome takes the (R)-configuration, whereas in the yeast proteasome it takes the (S)-configuration, indicating that the pre-chiral CHO group of 1 binds to the active site Thr1 in a different orientation. Re-examination of the structure of the yeast proteasome in complex with 1 showed significant conformational changes at the substrate-binding cleft along the active site. These structural differences are consistent with the different kinetic mechanisms of 1 against Mtb and human proteasomes.     

Calmodulin inhibitors from the fungus Emericella sp.

Two new xanthones identified as 15-chlorotajixanthone hydrate (1) and 14-methoxytajixanthone (2) were isolated from an Emericella sp. strain 25379 along with shamixanthone (3) and tajixanthone hydrate (4). The stereostructures of 1 and 2 were elucidated by spectroscopic and molecular modeling methods. The absolute configuration at the stereogenic centers of 1 was established according to CD measurements. In the case of 2, however, the absolute configuration at C-20 and C-25 was designated as S and R, respectively, by Mosher ester methodology. Thereafter, the configuration at C-14 and C-15 of 2 was established as S and S, respectively by comparing the optical rotation and ¹H–¹H coupling constant experimental values with those obtained through molecular modeling calculations at DFT B3LYP/DGDZVP level of theory for diasteroisomers 2a–2d. The activation of the calmodulin-sensitive cAMP phosphodiesterase (PDE1) was inhibited in the presence of 1–4 in a concentration-dependent manner. The effect of compounds 2 (IC₅₀ = 5.54 μM) and 4 (IC₅₀ = 5.62 μM) was comparable with that of chlorpromazine (CPZ; IC₅₀ = 7.26 μM), a well known CaM inhibitor used as a positive control. The inhibition mechanism of both compounds was competitive with respect to CaM according to a kinetic study. A docking analysis with 2 and 4 using the AutoDock 4.0 program revealed that they interacted with CaM in the same pocket as trifluoropiperazine (TFP).     

Cytotoxicity mechanisms of pyrazino[1,2-b]isoquinoline-4-ones and SAR studies

The cytotoxicity showed by 1b, an interesting representant of the title compounds, for HT-29 human colon cancer cells (CI₅₀ value of 1.95 × 10^?7 M) has been related to the induced cell death at the G2 phase and not to DNA damage. This compound promotes the degradation of components of the G2/M checkpoint machinery, in particular cdc2, Cyclin B1 and Wee1, which represents a novel mechanism of cytotoxicity. Degradation of Wee1 seems to be mediated by proteasome activity but degradation of cdc2 has to occur through a different mechanism. The activity of 1b on G2 cell cycle components suggests that tumor cells that are arrested in G2/M by anticancer drugs like cisplatin could be targeted by compound 1b, increasing the apoptosis induction, and that their optimized analogs might be useful in the treatment of colon cancer through combination therapies with cisplatin or other anticancer drugs that affect the cytoskeleton integrity such as taxol and taxotere.SAR studies with compounds obtained by manipulation of the N(2) and C(4)-functional groups and the C(6)-chain of compound 1b have confirmed the importance of these structural features in the in vitro antitumor activity. Fused oxazolidine derivatives as compound 5 were inactive, and the lack of activity found in the replacement of the C(4)-lactam by a cyanoamine function, as in compounds 8–10, could be explained considering that their all-syn relative configuration makes them too stable to generate alkylating iminium species.     

Sesquiterpenoids from the fruits of Alpinia oxyphylla and inhibition of nitric oxide production in lipopolysaccaride-activated macrophages

Three new norsesquiterpenoids, oxyphenol A (1), mandassion A (2) and mandassion B (3), along with three known compounds (4–6) were isolated from the fruits of Alpinia oxyphylla. Chemical structures of 1–3 were established by analysis of spectroscopic data. The absolute configuration of 2 and 3 was determined by the comparison of experimental electronic circular dichroism (ECD) spectroscopy and time-dependent density functional theory (TDDFT) calculations. Inhibitory effects of the six compounds on nitric oxide production in lipopolysaccaride-activated macrophages were evaluated, and compounds 3–5 showed significant inhibitory effect dependent on the concentration at the range of 1–50 μM.     

Biotransformation of natural compounds: Unexpected thio conjugation of Sch-642305 with 3-mercaptolactate catalyzed by Aspergillus niger ATCC 16404 cells

Sch-642305 is produced by the endophytic fungi Phomopsis sp. CMU-LMA and exhibits both antimicrobial and cytotoxic activities. The incubation of Sch-642305 with Aspergillus niger ATCC 16404 resting cells leads to two unexpected thio conjugates. Compound (1) is formed by the addition of the cysteine metabolite 3-mercaptolactate to the double bond of Sch-642305. Compound (1) undergoes an intramolecular rearrangement to give compound (2), which contains two rings: a five-membered hydroxylactone ring and a five-membered thiophene ring. The absolute configuration of compound (1) is similar to that of the parent compound, but the configuration of the mercaptolactate side-chain was not determined. The absolute configuration of compound (2) was deduced from the crystal structure and confirmed by the anomal effect of the sulfur atom. To the best of our knowledge, this is the first time such a conjugation rearrangement reactions were observed. The biological significance and the reaction mechanisms are discussed. Compound (1) exhibits a weak antimicrobial activity against Gram-positive bacteria, whereas derivatives (1) and (2) showed an IC₅₀ of 1 and 1.2 μM, respectively, against colonic epithelial cancer cells.     

N-Formyllapatin A,a new N-formylspiroquinazoline derivative from the marine-derived fungus Penicillium adametzioides AS-53

N-Formyllapatin A (1), a new spiroquinazoline derivative, and four known quinazoline metabolites, lapatins A (2) and B (3), prelapatin B (4), and glyantrypine (5), along with two known indolediketopiperazine derivatives, fumitremorgin B (6) and verruculogen (7), were characterized from Penicillium adametzioides AS-53, a fungus obtained from the fresh tissue of an unidentified marine sponge. The structure of compound 1 was established by detailed interpretation of NMR and MS data, and its absolute configuration was established by a single-crystal X-ray diffraction analysis. N-Formyllapatin A (1) represents the first N-formylspiroquinazoline secondary metabolite. Compounds 3 and 5–7 showed moderate inhibitory activity against aqua-pathogenic bacterial Vibrio harveyi.     

Xanthine oxidase inhibitors from an endophytic fungus Lasiodiplodia pseudotheobromae

Two new compounds, lasdiplactone (1) and lasdiploic acid (2) and one known compound 3 were isolated from the chloroform extract of cell free filtrate of the endophytic fungus Lasiosdiplodia pseudotheobromae. The structures of new compounds were determined by interplay of spectral techniques (IR, mass, ¹H NMR, ¹³C NMR, DEPT, and 2D NMR). The absolute configuration at C-4 position of 1 was established as S using a process similar to modified Mosher’s method. The absolute configuration of 2 was established by comparing its ECD spectrum with the calculated ECD spectra of all possible isomers. In the in vitro XO inhibition assay, the highest inhibition was exhibited by 3 with an IC₅₀ of 0.38 ± 0.13 μg/ml, followed by 2 with an IC₅₀ of 0.41 ± 0.1 μg/ml and the least in 1. The oxidized form of 1 also showed high XO inhibition with IC₅₀ of 0.35 ± 0.13 μg/ml.     

A new phenylpropanoid glycoside from the bark of Streblus ilicifolius (Vidal) Corner

A new compound, pheglycoside A (1), along with four known aromatic glycosides (2-5) and three known lignan glycosides (6–8) were isolated from Streblus ilicifolius (Vidal) Corner. The structure of compound 1 was determined by spectral analyses, including HRESIMS, 1D, and 2D NMR (COSY, HSQC, and HMBC) experiments. The absolute configuration of compound 1 was determined using the CD spectrum and experiment data. From the present investigation, all these compounds were isolated for the first time from S. ilicifolius. It is interesting that phenylpropanoid glycoside and aromatic glycosides are reported for the first time in the genus Streblus. The chemotaxonomic significance of these compounds was summarized.     

Novel spiro-sesquiterpene from the mushroom Anthracophyllum sp. BCC18695

A novel spiro-sesquiterpene, anthracophyllic acid (1), and a new aristolane sesquiterpene, anthracophyllone (2), were isolated from the mushroom Anthracophyllum sp. BCC18695, together with seven known compounds including aurisins A (3), G (4), K (5), nambinones A, C, axinysones A, and B. The relative configuration of 1 and the hitherto unknown absolute stereochemistry of 3 were determined based on X-ray spectroscopic data. Biological activities including antimalarial activity against Plasmodium falciparum K1 strain, antibacterial property against Bacillus cereus, and cytotoxicity against MCF-7, KB, NCI-H187, and Vero cells of the isolated compounds were also evaluated