Structure-based design,synthesis, and binding mode analysis of novel and potent chymase inhibitors

Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.     

Lignans from the fruit of Schisandra sphenanthera,and their inhibition of HSV-2 and adenovirus

The systematic isolation of the EtOAc extract from Schisandra sphenanthera fruit was performed during a search for HSV-2 and adenovirus inhibitors. Sixteen lignans were obtained, with compound 1 representing a new and rare type of lignan in the genus Schisandra. Their structures were elucidated by spectroscopy and comparison with literature data. Among all the lignans tested for their antiviral activities, compound 14 was the most active against HSV-2 with a selectivity index value up to 29.83. Moreover, the new compound 1, and the known ones (4, 6, 7, 10 and 14) also exhibited moderate inhibition of HSV-2 and adenovirus. To the best of our knowledge, this is the first report that these lignans from Schisandra genus were shown to have modest activity against HSV-2 and adenovirus. Meanwhile, structure–activity relationships of some lignans for the inhibitory activity against HSV-2 and adenovirus were discussed in this study.     

A new phenolic acid from Zanthoxylum nitidum var. tomentosum (Rutaceae) and its chemotaxonomic significance

A new compound, nitomentosin (1), along with sixteen known compounds (2–17), were isolated from Zanthoxylum nitidum var. tomentosum (Rutaceae). The structure of compound 1 including absolute configurations was determined by detailed spectroscopic information (HRESIMS and NMR) and from the electronic circular dichroism (ECD) spectra. From the present investigation, compound 3 is a new natural compound although it has been reported previously as a synthetic substance, and compound 15 is found for the first time in a plant. All these compounds except 2, 5–10 and 12 were isolated from Z. nitidum for the first time. Furthermore, the chemotaxonomic significance of the isolated compounds is discussed.     

Design,synthesis, and evaluation of novel inhibitors for wild-type human serine racemase

Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR.Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR.     

A new flavonoid from the stem bark of Acer tegmentosum

A new flavonoid, 6-carboxyl-(−)-catechin methyl ester (1) was isolated from the stem bark of Acer tegmentosum, along with six known flavonoids (2–7). The structure of compound 1 was determined by spectral analyses, including HR-ESI-MS, 1D and 2D NMR (COSY, HMQC and HMBC) experiments. From present investigation, compound 7 was isolated for the first time from the Aceraceae family.     

Chemical constituents from Eucalyptus citriodora Hook leaves and their glucose transporter 4 translocation activities

Bioassay-guided phytochemical investigation of the EtOAc fraction from the leaves of a Chinese medicinal herb, Eucalyptus citriodora Hook, resulted in the isolation of a new compound rhodomyrtosone E (1), along with 12 known compounds (2–13). The structure of the new compound was established by 1D and 2D NMR, MS data and X-ray crystallographic analysis. Betulinic acid (2) and corosolic acid (5) increased glucose transporter 4 (GLUT-4) translocation by 2.38 and 1.78-fold, respectively.     

Chemical constituents from Alnus mandshurica (Callier) Hand.-Mazz. and their chemotaxonomic significance

A new phenol compound, (9S)-9-hydroxy-9-[(2-hydroxyphenyl)methoxy]-nonanoic acid methyl ester (1) was isolated from the stem bark of Alnus mandshurica (Callier) Hand.-Mazz., along with eight known compounds (2–9). The structure of compound 1 was determined by spectral analyses, including HR-ESI-MS, 1D and 2D NMR (COSY, HMQC and HMBC) experiments. All the isolated compounds were reported for first time from A. mandshurica. Furthermore, compounds 3–9 were found in the family Betulaceae for the first time.     

A new sesquiterpenoid from Sclerorhachis platyrachis (Boiss.) Podlech ex Rech.f

A new eudesmane-type sesquiterpenoid together with two known flavonoids were isolated from the chloroform extract of the aerial part of Sclerorhachis platyrachis. The structure of the new compound was deduced from its comprehensive spectroscopic analysis including IR, EI-MS, ¹H NMR, ¹³C NMR, DEPT, COSY, HMBC and HMQC and was shown to be 4R^*-hydroxy-6S^*-tigloyloxyeudesma-7S^*-11 (13)-en-12-oic acid (1). Finally, the structure of the new compound was unambiguously confirmed by single-crystal X-ray analysis. The structure of known compounds 2 and 3 were identified by comparison of their spectral data with those reported in the literature.     

Isolation,structural elucidation,and insights into the anti-inflammatory effects of triterpene saponins from the leaves of Stauntonia hexaphylla

Using various chromatographic techniques, 23 triterpene saponins (1–23) were isolated from an ethanol extract of Stauntonia hexaphylla, including two new compounds (12 and 15). Their chemical structures were established by comprehensive spectroscopic methods such as 1D- and 2D-NMR, and HR-ESI-MS, and chemical reactions. The anti-inflammatory activities of the isolated saponins were determined using the nitric oxide (NO) assay. Compound 13 exhibited the greatest inhibitory effect (IC₅₀?=?0.59?μM). In addition to NO, compound 13 suppressed the secretion of PGE₂, IL-1β, and IL-6, but not TNF-α, and inhibited the protein expression of iNOS and COX-2 in LPS-activated RAW264.7 cells. The chemical derivatives of the isolated compounds were studied using structure–activity relationships. The results suggested that compound 13 isolated from S. hexaphylla might be useful for treating inflammation. This is the first comprehensive study of saponins from the leaves of S. hexaphylla based on anti-inflammatory extract screening guidelines.     

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.     

Synthesis of polyozellin,a prolyl oligopeptidase inhibitor,and its structural revision

Polyozellin is a p-terphenyl compound which was isolated from Polyozellus multiplex, and exhibits an inhibitory activity against prolyl oligopeptidase (POP). Its structure was assigned as 1 having a p-terphenyl skeleton including a p-substituted dibenzofuran moiety by spectroscopic analyses and chemical means. This paper describes the total syntheses of the proposed structure 1 for polyozellin and its o-isomer 2, revising the structure of polyozellin to the latter. These syntheses involved a double Suzuki-Miyaura coupling using chlorophenylboronic acid as a common key building block, and Cu mediated Ullmann cyclization as key steps. The inhibitory activities of synthetic compounds against POP and cancer cells were also evaluated.     

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.     

Antitumor antibiotics drug design. Part II. Synthesis of 4-ethylamido [5,(2′-thienyl)-2-thiophene] imidazole iron(II) complex,a new N2S2-metallocycle with a ‘built in’ intercalating moiety which causes DNA scissioning In Vitro

A new metal chelating moiety, 4-ethylamido [5,(2′- thienyl)-2-thiophene]imidazole iron(II) (1) was synthesized and showed antitumor activity in vitro. The bisthiophene moiety which sterically resembles the bithiazole units of bleomycin may allow us to probe further the mechanism of antitumor action by bleomycin. The cyclic voltammetry for the new compound 1 in DMSO showed a nearly reversible Fe³⁺/Fe²⁺ transition. The electron spin resonance spectrum consisted of a fairly broad band resonance centered at g = 2.00989, similar to that of a bleomycin-Fe²⁺ complex. The new compound 1 causes cleavage of double helical DNA without the requirement of an extra intercalating group.     

Synthesis of the 3- and 4-methyl, 3,4-dimethyl, and 3,4,6-trimethyl ethers of methyl 2-acetamido-2-deoxy-alpha-D-mannopyranoside

The methyl ethers of 2-amino-2-deoxy-D-mannose are reference compounds in studies, by the methylation procedure, of the chemical structure of polysaccharides containing 2-amino-2-deoxy-D-mannose and 2-amino-2-deoxy-D-mannuronic acid residues. Methylation of methyl 2-acetamido-2-deoxy-α-D-mannopyranoside (1) gave the 3,4,6-trimethyl ether. Methylation of the 6-trityl ether of 1, followed by detritylation, gave the 3,4-dimethyl ether of 1. Methylation of the 4,6-O-benzylidene derivative (6) of 1, followed by removal of the benzylidene group, gave the 3-methyl ether of 1. Benzoylation of 6, followed by removal of the benzylidene group and monobenzoylation, gave the 3,6-dibenzoate of 1, which was methylated, and the product saponified, to give the 4-methyl ether of 1; the latter compound was also obtained by a similar route via the 3-O-acetyl-6-O-benzoyl derivative.     

Leupeptazin,a highly modified tripeptide isolated from cultures of a Streptomyces sp. inhibits cathepsin K

Using a human cathepsin K-targeting inhibitor screen, a new leupeptin analogue, leupeptazin (1), containing an unprecedented piperidinotriazine moiety, was isolated from a liquid culture of soil Streptomyces sp. IS2-4 collected in northern Italy. The structure of leupeptazin was established using HRESIMS as well as 1D and 2D NMR data. The inhibitory activity of the compound towards the collagenase cathepsin K was tested in vitro to reveal moderate activity with an inhibition constant, K_i, of 44 μM.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Sannastatin, a novel toxic macrolactam polyketide glycoside produced by actinomycete Streptomyces sannanensis

A new rare 20-membered macrocyclic lactam incorporating a diene conjugated olefin, designated sannastatin (1), together with the known structurally related vicenistatin (2), has been isolated from the cultures of Streptomyces sannanensis, a bacteria found in the feces of Ailuropoda melanoleuca. The structure of the new compound was established on the basis of extensive spectroscopic analyses including 1D- and 2D-NMR (¹H-¹H COSY, TOCSY, HSQC, HMBC, and NOESY) experiments. Compounds 1 and 2 displayed significant growth inhibitory activity against the brine shrimp (Artemia salina) larvae.     

A lanostane aldehyde from Momordica charantia

A new lanostane aldehyde, charantal (1), was isolated from the ethanolic leaf extract of Momordica charantia together with the known compound, 2,4-bis(2-phenylpropan-2-yl)phenol (2). The structure of compound 1 was elucidated by extensive 1D and 2D NMR and MS experiments. Compound 2 displayed a moderately strong antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MIC = 14 μg/mL) according to the MABA susceptibility assay.     

Two new pyrrole derivatives isolated from Salacia amplifolia Merr

Two new pyrrole derivatives Salaciamole (1), Salaciaglycoside A (2), long with one known compound 1H-pyrrole-3-carboxylic acid (3) were isolated from the roots of Salacia amplifolia Merr (Hippocrateaceae). The structures of the new compounds were deduced from their comprehensive spectroscopic analysis including IR, HR-EI-MS, ¹H NMR, ¹³C NMR, DEPT, COSY, HMBC and HMQC. And the structure of the known compound was identified by comparison of their spectral data with those reported in the literature.     

Cordylactam,a new alkaloid from the spider pathogenic fungus Cordyceps sp. BCC 12671

Cordylactam (1), a new lactam-fused 4-pyrone was isolated from the spider pathogenic fungus Cordyceps sp. BCC 12671. The structure was elucidated on the basis of NMR spectroscopic and mass spectrometry data, which was further confirmed by the spectroscopic analyses of a semisynthetic derivative. This is the first report of a new compound from spider pathogenic Cordyceps species.