Absolute Configurations and Chitinase Inhibitions of Quinazoline-Containing Diketopiperazines from the Marine-Derived Fungus Penicillium polonicum.

Three new quinazoline-containing diketopiperazines, polonimides A-C (1-3), along with four analogues (4-7), were obtained from the marine-derived fungus Penicillium polonicum. Among them, 2 and 4, 3 and 5 were epimers, respectively, resulting the difficulty in the determination of their configurations. The configurations of 1-3 were determined by 1D nuclear overhauser effect (NOE), Marfey and electron circular dichroism (ECD) methods. Nuclear magnetic resonance (NMR) calculation with the combination of DP4plus probability method was used to distinguish the absolute configurations of C-3 in 3 and 5. All of 1-7 were tested for their chitinase inhibitory activity against OfHex1 and OfChi-h and cytotoxicity against A549, HGC-27 and UMUC-3 cell lines. Compounds 1-7 exhibited weak activity towards OfHex1 and strong activity towards OfChi-h at a concentration of 10.0 µM, with the inhibition rates of 0.7%-10.3% and 79.1%-95.4%, respectively. Interestingly, 1-7 showed low cytotoxicity against A549, HGC-27 and UMUC-3 cell lines, suggesting that good prospect of this cluster of metabolites for drug discovery.

Dipleosporalones A and B, Dimeric Azaphilones from a Marine-Derived Pleosporales sp. Fungus.

Dipleosporalones A and B (1 and 2), two new [2 + 2] azaphilone dimers, were obtained from a marine-derived Pleosporales sp. fungus. The absolute configurations of 1 and 2 were elucidated by calculations of their ECD spectra. Dipleosporalone A (1) possessed an unprecedented skeleton with an uncommon 6/4/6 ring system. Compounds 1 and 2 showed cytotoxicity about 30-90-fold more potent than that of their monomer pinophilin B.

Asperienes A-D, Bioactive Sesquiterpenes from the Marine-Derived Fungus Aspergillus flavus.

Marine-derived fungi of the genera Aspergillus could produce novel compounds with significant bioactivities. Among these fungi, the strain Aspergillus flavus is notorious for its mutagenic mycotoxins production. However, some minor components with certain toxicities from A. flavus have not been specifically surveyed and might have potent biological activities. Our investigation of the marine-derived fungus Aspergillus flavus CF13-11 cultured in solid medium led to the isolation of four C-6'/C-7' epimeric drimane sesquiterpene esters, asperienes A-D (1-4). Their absolute configurations were assigned by electronic circular dichroism (ECD) and Snatzke's methods. This is the first time that two pairs of C-6'/C-7' epimeric drimane sesquiterpene esters have successfully been separated. Aperienes A-D (1-4) displayed potent bioactivities towards four cell lines with the IC50 values ranging from 1.4 to 8.3 µM. Interestingly, compounds 1 and 4 exhibited lower toxicities than 2 and 3 toward normal GES-1 cells, indicating more potential for development as an antitumor agent in the future.

Discovery of Bioactive Indole-Diketopiperazines from the Marine-Derived Fungus Penicillium brasilianum Aided by Genomic Information.

Identification and analysis of the whole genome of the marine-derived fungus Penicillium brasilianum HBU-136 revealed the presence of an interesting biosynthetic gene cluster (BGC) for non-ribosomal peptide synthetases (NRPS), highly homologous to the BGCs of indole-diketopiperazine derivatives. With the aid of genomic analysis, eight indole-diketopiperazines (1-8), including three new compounds, spirotryprostatin G (1), and cyclotryprostatins F and G (2 and 3), were obtained by large-scale cultivation of the fungal strain HBU-136 using rice medium with 1.0% MgCl2. The absolute configurations of 1-3 were determined by comparison of their experimental electronic circular dichroism (ECD) with calculated ECD spectra. Selective cytotoxicities were observed for compounds 1 and 4 against HL-60 cell line with the IC50 values of 6.0 and 7.9 µM, respectively, whereas 2, 3, and 5 against MCF-7 cell line with the IC50 values of 7.6, 10.8, and 5.1 µM, respectively.

Four new antitumor metabolites isolated from a mutant 3-f-31 strain derived from Penicillium purpurogenum G59.

Penicimutanolones A (1) and B (2), penicimutanolone A methyl ether (3), and penicimumide (4), four new antitumor metabolites, were isolated from a neomycin-resistant mutant of the marine-derived fungus Penicillium purpurogenum G59. The structures of the compounds were elucidated by spectroscopic methods, and the absolute configurations were determined by X-ray crystallography and calculated ECD. In MTT and SRB assays, compounds 1-3 showed strong inhibitory effects on 14 human cancer cell lines. Compounds 1 and 2 maybe induce apoptosis of cancer cells mainly due to the inhibition of the expression of survivin, a client protein of HSP90. In addition, in vivo antitumor activity was observed for compound 1 in murine sarcoma HCT116 tumor-bearing Kunming mice, using docetaxel as a positive control.

Absolute Configurations of 14,15-Hydroxylated Prenylxanthones from a Marine-Derived Aspergillus sp. Fungus by Chiroptical Methods.

Determination of the absolute configrations for natural products is one of the most important and challenging tasks, especially when the molecules display high conformational flexibility. In this paper, eight new prenylxanthones, aspergixanthones A-H (1-8), and one known analogue (9), were isolated from the marine-derived fungus Aspergillus sp. ZA-01. The absolute configurations of C-14 and C-15 in 1-8 were difficult to be assigned due to the high conformational flexibility of the chains. To solve this problem, the experimental ECD, ORD, and VCD spectra of 1 were combined for analysis with the corresponding theoretical predictions for its different diastereomers. This study suggested that a concerted application of more than one chiroptical methods could be used as a preferable approach for the stereochemical characterizations of flexible molecules. Compounds 1-9 were evaluated for their cytotoxic and antibacterial activities. Among them, 6 showed cytotoxicity against the A-549 cell line with the IC50 value of 1.1 µM, and 7 exhibited antibacterial activity against Micrococcus lysodeikticus with the MIC value of 0.78 µg/mL.

Cytotoxic Serrulatane-Type Diterpenoids from the Gorgonian Euplexaura sp. and Their Absolute Configurations by Vibrational Circular Dichroism.

Vibrational circular dichroism (VCD) method has become robust and reliable alternative for the stereochemical characterization of natural products. In this paper, three new serrulatane-type diterpenoids, euplexaurenes A-C (1-3), and a known metabolite, anthogorgiene P (4), were obtained from the South China Sea gorgonian Euplexaura sp. GXWZ-05. The absolute configuration of C-11 in 1-4, which was difficult to be determined by common means due to the high conformational flexibility of the eight-carbon aliphatic chain attached at C-4, was determined by VCD method, suggesting a new horizon to define the absolute configurations of natural products possessing chains. Compounds 1-4 were found to show selective cytotoxic activities against human laryngeal carcinoma (Hep-2) cell line with the IC50 values of 1.95, 7.80, 13.6 and 5.85 µM, respectively.

Bioactive phenyl ether derivatives from the marine-derived fungus Aspergillus carneus.

A new phenyl ether derivative, 3-hydroxy-5-(3-hydroxy-5-methylphenoxy)-4-methoxybenzoic acid (1), along with two known analogues, 3,4-dihydroxy-5-(3-hydroxy-5-methylphenoxy)benzoic acid (2) and 3-hydroxy-5-(3-hydroxy-5-methylphenoxy)benzoic acid (3), were isolated from the fungus Aspergillus carneus collected from South China Sea. The structure elucidation of 1 was determined based on extensive NMR and MS spectroscopic analyses. Compound 2 showed a strong antioxidant activity with an IC50 value of 19.3 µM which was close to the positive control ascorbic acid (IC50 = 15.3 µM).

Syntheses of novel ß-carboline derivatives and the activities against five tumor-cell lines.

A series of ß-carbolines possessing the aryl group at C-1 position has been synthesized from tryptophan. The newly synthesized compounds were screened for their in vitro anticancer activity against various human cancer cell lines by MTT assay. Some of them exhibited anticancer activity with IC50 values lower than 10µM outdistanced the cisplatin level. Structure-activity relationship reveals that the alcohol substituents at C-3 position played an important role in inhibition activity.

A new spirocyclic compound from the liquid culture of entomogenous fungus Isaria cateniannulata.

A new spirocyclic compound named (2S, 5S, 7S)-3α-hydroxyl-exogonic acid (1) was isolated from the liquid culture of entomogenous fungus Isaria cateniannulata. The structure and relative stereochemistry of 1 were elucidated by extensive spectroscopic analysis and by comparison of its NMR data with those of known compound. Compound 1 showed weak inhibitory activity against HeLa with IC(50) value of 80.5 µg ml(- 1).

Griseusins F and G, spiro-naphthoquinones from a tin mine tailings-derived alkalophilic Nocardiopsis species.

Griseusins F (1) and G (2), two 2a-hydro-8a-(2-oxopropyl)-substituted spiro-naphthoquinones with a previously undescribed C23 polyketide skeleton, were isolated from a Yunnan tin mine tailings-derived alkalophilic actinomycete, Nocardiopsis sp. YIM DT266. Their complete structure assignments with the absolute stereochemistry were elucidated by spectroscopic data, X-ray crystal diffraction, calculation of optical rotation, and CD spectroscopic analysis. Compounds 1 and 2 exhibited strong cytotoxicity (IC50 0.37-0.82 µM) and antibacterial activity (MIC 0.80-1.65 µg/mL) against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) in vitro.

Sesquiterpenoids from Incarvillea arguta: absolute configuration and biological evaluation.

Diincarvilones A-D (1-4), incarvilone A (5), and a known compound, argutosine B (6), were isolated from Incarvillea arguta. The structures, including the absolute configurations of the new compounds, were determined by NMR spectroscopy, X-ray diffraction analysis, CD spectroscopy, and a variety of computational methods. The biological properties of these substances, including effects on intracellular Ca(2+) influx, nitric oxide (NO) production, and human cancer cells, were evaluated. The results showed that at the concentration of 10 µM (in HBSS buffer) diincarvilones A and B cause a persistent increase in cytoplasmic calcium levels in A549 cells.

Psychotripine: a new trimeric pyrroloindoline derivative from Psychotria pilifera.

Psychotripine, a trimeric pyrroloindoline derivative with an unprecedented hendecacyclic system bearing a hexahydro-1,3,5-triazine unit, was isolated from the leaves of Psychotria pilifera. The structure was elucidated on the basis of spectroscopic and quantum theory. A possible biogenesis was also postulated.

Design, synthesis and cytotoxic activities of novel ß-amino alcohol derivatives.

Three series of novel ß-amino alcohols possessing an N-anthranyl group have been obtained using tryptophan as the major starting material. These compounds were screened for cytotoxic activity against five human cancer cell lines in vitro by MTT assay, and some of them exhibited potential ability to be anticancer agents. Structure-activity relationship was carefully investigated. Only the compounds possessing small substituents (H or CH(3)) at C-6 position showed the same activity as cisplatin (DDP) did.

A pair of windmill-shaped enantiomers from Lindera aggregata with activity toward improvement of insulin sensitivity.

(+)-Linderaspirone A and (-)-linderaspirone A, a pair of natural windmill-shaped enantiomers, were isolated from the traditional Chinese medicine plant Lindera aggregate by HPLC using a chiral column, achieving over 98% ee. Their structures and absolute configurations were determined on the basis of extensive analysis of NMR spectra, crystal X-ray diffraction, and calculation of the optical rotations (OR). They have an unprecedented carbon skeleton and showed significant activity against glucosamine-induced insulin resistance.

Compounds from Acorus tatarinowii: determination of absolute configuration by quantum computations and cAMP regulation activity.

A new cadinane-type sesquiterpenoid, tatarinowin A (1), two phenylpropanoids, tatarinoids A (2) and B (3), and a trinorlignan, tatarinoid C (4), along with 15 known compounds including two pairs of mixtures were isolated from the rhizome of Acorus tatarinowii. The absolute configurations of 1-4 were established by computation of specific rotation values. The isolated compounds were evaluated for their cAMP regulatory activity by the AlphaScreen assay.

Diterpenoids from the feces of Trogopterus xanthipes.

Three new isopimarane diterpenoids, trogopteroids A-C (1-3), four new aromatic diterpenoids, trogopteroids D-G (4-7), and 12 known diterpenoids were isolated from the feces of Trogopterus xanthipes. Their structures were identified using spectroscopic methods. The relative configuration of 1 was confirmed by quantum calculations. Compound 1 represents the first example of a norisopimarane diterpenoid with an 8alpha,15alpha-olide ring. With the exception of compound 14, all diterpenoids were evaluated for cytotoxicity against seven human tumor cell lines.

Velleratretraol, an unusual highly functionalized lactarane sesquiterpene from Lactarius vellereus.

An unusual highly functionalized lactarane sesquiterpene, named velleratretraol (1), was isolated from the ethanol extract of the fruiting body of the mushroom Lactarius vellereus. Its structure was determined through spectroscopic analysis and single-crystal X-ray diffraction studies. The proposed assignment of the absolute configuration is based on computational results. It showed weak activity against HIV-1 cells with an effective concentration of 68.0 microg ml(-1) and a selectivity index of 2.0.

Structure elucidation and theoretical investigation of key steps in the biogenetic pathway of schisanartane nortriterpenoids by using DFT methods.

Rubrifloradilactone C (4), a novel bioactive nortriterpenoid, along with four other nortriterpenoids (1-3, 5) were isolated from Schisandra rubriflora. The structure of 4 was determined by extensive NMR spectral analysis, computational evidence by using the GIAO method at the B3LYP/6-311++G(2d,p)//B3LYP/6-31G(d) levels, and X-ray analysis. DFT at the B3LYP/6-311+G(d,p) level was selected to clarify the key mechanistic steps in the formation of 1 and 4 through transition-state (TS) investigations. The effect of enzymes on the TS barriers was considered by using the polarized continuum model. Other possible products based on the new mechanism were predicted.

Synthesis and anticancer activity of lipophilic platinum(II) complexes of 3,5-diisopropylsalicylate.

Novel lipophilic platinum(II) complexes (LSPt-1-3), containing 3,5-diisopropylsalicylate (DIPS) as a leaving group and 2NH(3) or 1R,2R-diaminocyclohexane or (4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane as the carrier, have been synthesized, characterized and evaluated in vitro and in vivo. The octanol/water distribution coefficient of the complexes has also been measured. The results showed that the complexes achieved a typical square planar and the octanol/water distribution coefficient logP was 4.27, 4.37 and 4.31. The complexes were tested by SRB method to be more cytotoxic than Carboplatin, Oxaliplatin and Eptaplatin against 3AO, A549, NCI-H460 and SGC-7901 human cancer cell lines. Among complexes, LSPt-2 was much more effective than Carboplatin and Oxaliplatin in treating the NCI-H460 non-small-cell lung tumor-bearing mice. Its optimal activity was 38.8% (T/C) at a dose of 30 mg/kg following i.p. administration. LD(50) for the complex was found to be 230.9 mg/kg. LSPt-2 exhibited great anticancer activity, good lipophilic ability and low toxicity and therefore, it is a promising candidate for effective and stable pharmaceutical liposomal platinum anticancer drug.