Design and synthesis of highly selective pyruvate dehydrogenase complex E1 inhibitors as bactericides

In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking. The newly introduced acylhydrazone and N-phenylbenzamide moieties could form stronger interaction by hydrogen bond at the active site of E. coli PDHc-E1 compared with that of porcine PDHc-E1. A part of title compounds as potent PDHc-E1 inhibitors also exhibited notable antibacterial activity. In particular, 12e, 12f, 12g, 12o, and 19a exhibited 72–92% inhibition against Xanthomonas oryzae pv. Oryzae and Ralstonia solanacearum at 100?μg/mL, which was better than thiodiazole-copper (34 and 29%, respectively) and bismerthiazol (56 and 55%, respectively). The results proved that we could obtain effective bactericidal compounds as highly selective PDHc inhibitors by rational molecular design utilizing the binding model of active site of E. coli PDHc-E1.     

Inhibition of antigen-induced degranulation by aryl compounds isolated from the bark of Betula platyphylla in RBL-2H3 cells

The methanolic extract of the bark of Betula platyphylla was found to suppress antigen mediated degranulation of RBL-2H3 cells. Four arylbutanoids (1–4) and eight diarylhepatonoids (5–12) were isolated from the methanolic extract using bioassay-guided fractionation. Among them, compounds 4 and 12 were isolated and assigned for the first time. Compounds 1, 2, 3, 5, 10, and 12 showed remarkable inhibitory activity against the degranulation of RBL-2H3 by antigen stimulation in a dose dependent manner at the concentrations ranging from 10 μM to 100 μM.     

Protective effect of lanostane triterpenoids from the sclerotia of Poria cocos Wolf against cisplatin-induced apoptosis in LLC-PK1 cells

Cisplatin-induced nephrotoxicity is a serious adverse effect that limits the use of cisplatin in cancer patients. In the present study, we investigated the protective effect of lanostane triterpenoids (1–10) isolated from the ethanolic extract of Poria cocos Wolf against cisplatin-induced cell death in LLC-PK1 kidney tubular epithelial cells. Treatment of cisplatin induced significant cell death, which was suppressed by treatment with dehydroeburicoic acid monoacetate (1) and 3β-acetoxylanosta-7,9(11),24-trien-21-oic acid (9). Compound 1 exhibited the highest efficacy among the tested compounds and was thus subjected to further mechanistic studies. The increase in the percentage of apoptotic cells induced by cisplatin reduced by 4.3% after co-treatment of cells with compound 1 (50 and 100 μM). Furthermore, phosphorylation of the mitogen-activated protein kinases JNK, ERK, and p38, and caspase-3, which characterize oxidative stress-mediated apoptosis, increased significantly after treatment with cisplatin, and decreased after treatment with compound 1. These results indicate that the renoprotective effects of compound 1 may be mediated by its anti-apoptotic activity.     

Chemical constituents from Cymbaria dahurica L. (Scrophulariaceae)

Phytochemical study of Cymbaria dahurica L. afforded 16 compounds, including 12 flavonoids (1–12) and 4 iridoids (13–16). Structure elucidation of these compounds was generated by a combination of spectroscopic means (ESI-MS, ¹H and ¹³C NMR) and comparisons with the published data. This is the first report of isolation of compounds (1–6, 10–16) from C. dahurica and compounds (5, 10, 12) from the family Scrophulariaceae, respectively. The chemotaxonomic data can support the genus Cymbaria being accepted as a member of transitional taxa between the family Scrophulariaceae and Orobanchaceae.     

Phytochemical and chemotaxonomic study on the Lichen Lethariella cladonioides

The comprehensive phytochemical research of Lethariella cladonioides (Nyl.) Krog, (Parmeliaceae), a lichen in southwest China, resulted in isolation of eighteen compounds (1–18), including a new phenolic acid 3,5-dihydroxy-4-methylbenzaldehyde (1) and seventeen known compounds, nine phenolic acids (2–10), one dibenzofuran (11), two depsides (12 and 13), one alkane (14), one glucoside (15), two polyols (16 and 17), and one fatty acid (18). The structures of these compounds were assigned by detailed interpretations of spectroscopic data (1D and 2D NMR, HR-ESI-MS) and comparisons with the published data. Among them, 3,5-dihydroxy-4-methylbenzaldehyde (1) is a new one. (−)-hydroxypropan-2′,3′-diol-orsellinate (10) have not been reported from any species in the lichens. Compounds 6, 7, 9, 12, 14, 16 and 18 were firstly isolated from the genus Lethariella (Motyka) Krog. Compounds 2, 6, 7, 9, 10, 12, 14, 16 and 18 were reported from L. cladonioides firstly. The chemotaxonomic significance of these compounds was also discussed.     

Biotransformation of chinensiolide B and the cytotoxic activities of the transformed products

Biotransformation of chinensiolide B, 10α-hydroxy-1α,5α,15-H-3-oxoguaia-11(13)-en-6α,12-olide (1), yielded three selectively reduced products, 3β,10α-dihydroxy-1α,5α,15α-H-guaia-11(13)-en-6α,12-olide (2), 3α,10α-dihydroxy-1α,5α,15α-H-guaia-11(13)-en-6α,12-olide (3), and 3β,10α-dihydroxy-1α,5α,11β,15α-H-guaia-6α,12-olide (4) by the cell suspension cultures of Catharanthus roseus. 2 and 3 were also obtained from 1 incubated with cell cultures of a fungus Abisidia coerulea IFO 4011 and Platycodon grandiflorum, respectively. Among them, 2, 3 are two new compounds. The three products, 2–4, along with 1 were preliminarily evaluated for their in vitro cytotoxic activity against 3 cell lines (HepG2, WI-38 and VA-13) and all showed potent inhibitory effects on the cell proliferation. Of the four compounds, 3 was the most toxic to the three cell lines tested with IC₅₀ values of 22.7, 0.33 and 3.30 μM, respectively.     

Chemical constituents from Phlomis bovei Noë and their chemotaxonomic significance

A phytochemical investigation of the leaves and roots of Phlomis bovei Noë (Lamiaceae) led to the isolation of sixteen compounds, including iridoids (1, 2, 3), megastigmanes (4, 5), phenylpropanoids (6, 7, 8, 9, 10), lignans (11, 12, 13, 14), a nortriterpene (15), and a phenyl glucoside (16). Compounds (1, 2, 4, 5, 6, 10) were obtained from the leaves and compounds (1, 2, 3, 7, 8, 9, 11, 12, 13, 14, 15, 16) were isolated from the roots. Compounds 1 and 2 were found both in the leaves and in roots.The compounds were identified by analysis of 1D- (¹H, ¹³C), 2D-NMR (¹H–¹H COSY, TOCSY, ROESY, HSQC, HMBC) spectroscopic data, mass spectrometry (ESI- and HR-ESI-MS), and by comparison with previously reported spectral data.Compounds 5, 9, 10, 13 and 14 were isolated from the genus Phlomis for the first time. All these specialized metabolites were described here for the first time in the Algerian Phlomis bovei Noë species. To the best of our knowledge, no reports have appeared on the constituents of the roots of P.bovei Noë. The chemotaxonomic significance of these compounds was summarized.     

Flavonoids and phenolic acids from the roots of Sophora tonkinensis Gagnep

Phytochemical study on the roots of Sophora tonkinensis Gagnep. led to the isolation of fifteen compounds, including eleven flavonoids (1–11) and four phenolic acids (12–15). The structures of these compounds were elucidated based on NMR and HR-ESIMS analysis, further supported by comparison with previous literatures. Among them, compounds 2, 3, 4, 6, 9, 12 and 13 were firstly discovered from S. tonkinensis, compound 8 was firstly discovered from the genus Sophora. Furthermore, the chemotaxonomic significance of the obtained compounds was discussed in detail.     

New derivatives of ursolic acid through the biotransformation by Bacillus megaterium CGMCC 1.1741 as inhibitors on nitric oxide production

Microbial transformation of ursolic acid (1) by Bacillus megaterium CGMCC 1.1741 was investigated and yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (2); 1β,11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3); 1β-hydroxy-3-oxo-urs-12-en-28, 13-lactoe (4); 1β,3β, 11α-trihydroxyurs-12-en-28-oic acid (5) and 1β,11α-dihydroxy-3-oxo-urs-12-en-28-O-β-d-glucopyranoside (6). Metabolites 3, 4, 5 and 6 were new natural products. Their nitric oxide (NO) production inhibitory activity was assessed in lipopolysaccharide (LPS) – stimulated RAW 264.7 cells. Compounds 3 and 4 exhibited significant activities with the IC₅₀ values of 1.243 and 1.711 μM, respectively. A primary structure-activity relationship was also discussed.     

Chemical constituents from the pericarps of Zanthoxylum bungeanum and their chemotaxonomic significance

The phytochemical study of the pericarps of Zanthoxylum bungeanum Maxim under the guidance of bioactivity led to the isolation of 18 compounds, including a new isobutylhydroxyamide (1) and 17 known compounds, i.e. six alkylamides (2–7), five coumarins (8–12), one benzene derivative (13), three flavonoids (14–16), and two sterols (17–18). Their structures were elucidated based on extensive spectroscopic methods (HRESIMS, 1D and 2D NMR experiments) and by comparison with literature data. New compound (1) and known compound (2) are cis-trans isomeric isobutylhydroxyamides. Among them, compounds 9, 10, and 12 were isolated for the first time from Z. bungeanum, compound 11 was firstly recovered from the genus Zanthoxylum, and compound 14 was reported for the first time from the Rutaceae family. The chemotaxonomic significance of isolated compounds from Z. bungeanum is discussed.     

Chemical constituents of Peperomia tetraphylla (Forst. F.) Hooker et Arnott

Sixteen compounds were isolated from the whole herbs of Peperomia tetraphylla (Forst. F.) Hooker et Arnott by phytochemical methods, including eight flavonoids (1–3, 6, 7, 14–16), three lignans (8–10), three beta sitosterols (4, 5, 11), and two phenolic acids (12, 13). Their structures were identified by the analysis of NMR and MS, as well as the comparisons to the reported data. Among them, 2″-O-xylosylisoswertisin (14) was firstly isolated from the Piperaceae family, as well as ten compounds (1–4, 7, 10–11, 13, 15–16) were isolated from P. tytraphylla for the first time. Moreover, the chemotaxonomic significance of constituents isolated from P. tytraphylla was also discussed.     

Cycloartane-type triterpenoids and sesquiterpenoids from the resinous exudates of Commiphora opobalsamum

Cycloartane-type triterpenoids (1–3), seven sesquiterpenoids (7–13), and five previously reported secondary metabolites, including three cycloartane-type triterpenoids (4–6) and two sesquiterpenoids (14 and 15), were isolated from the resinous exudates of Commiphora opobalsamum. Their structures were elucidated by extensive spectroscopic analysis, including UV, IR, NMR, and MS, and comparison with literature data. The structures of 1, 3, and 7 were confirmed by single-crystal X-ray diffraction analysis. The absolute configuration of 1 was interpreted by the incorporation of CHCl₃ (crystallization solvent) in the crystal and that of 10 was determined by the CD exciton chirality method. Compound 12 represents the first example of a 12-norcadinane-type sesquiterpenoid. Furthermore, compounds 1, 3, 7, and 10–14 were evaluated for cytotoxicity against HeLa and HepG2 cell lines.     

Chemical constituents from the roots of Elephantopus scaber L.

A chemical investigation of the roots of Elephantopus scaber L. led to the isolation of thirteen compounds, including four sesquiterpenoids (5, 6, 7, 8), two phenols (1, 2), three triterpenoids (9, 10, 11), two caffeoylquinic acids (3, 4), one alkaloid (12), and one sterol (13). Among these molecules, compound 2 (2-butenoic acid, 3-methyl-[4-(1,5-dimethyl-4-hexenyl)-3-hydroxyphenyl] methyl ester) was identified for the first time from this species, while compounds 1 (curcuphenol) and 12 (patriscabratine) were isolated for the first time from the genus Elephantopus.     

Coumarins and other components of Daphne oleoides Schreb. subsp. oleoides from Majella National Park

The present study reports about the phytochemical analysis of a sample of Daphne oleoides Schreb. subsp. oleoides (family Thymelaeaceae) collected from the Majella National Park. Twenty components, belonging to different classes of natural products, have been identified by means of spectroscopic and spectrometric techniques: [monomeric (4), bis- (5, 7–10, 20) and trimeric coumarins (11), including aglycones and glycosides, coumarinolignoid (6); flavonoids (16–19); glycosidic furolignans (14, 15), glucosidic phenylpropanoids (12, 13), cyclic tetrapyrrole derivatives (2, 3), unsaturated triglyceride (1)]. Besides the chemosystematic markers of the genus (4–10, 12, 14–18, 20) several other components were identified for the first time in the species (17, 20) and/or in the Daphne genus (1–3, 13, 19). The observed composition was discussed from the chemotaxonomic standpoint and compared with those recognized from a Sardinian accession. It was observed a pronounced difference in the two metabolites patterns, most probably attributable to geographic isolation of the studied populations and, in some extent, also by the different environmental conditions, evidencing a possible tendency of D. oleoides to the infraspecific chemovariability. Considering the wide traditional uses of Daphne spp. in ethnomedicine of several countries, also the pharmacologic potential of the identified secondary metabolites is discussed.     

Flavonoids and polyacetylenes from the aerial parts of Bidens tripartita

Fourteen flavonoids (1–14) and two polyacetylenes (15 and 16) were isolated from the aerial parts of Bidens tripartita. Thirteen compounds (1–7, 9, 11, 12, and 14–16) were isolated from this species for the first time, of which a flavonoid (11) was obtained for the first time from the genus Bidens. The chemotaxonomic significance of these compounds was summarized.     

Bioactive oleanane-type saponins from the rhizomes of Anemone taipaiensis

Investigation of the n-BuOH extract of the rhizomes of Anemone taipaiensis led to the isolation of five new oleanane-type triterpenoid saponins (1–5), together with seven known saponins (6–12). Their structures were determined by the extensive use of ¹D and ²D NMR experiments along with ESIMS analyses and acid hydrolysis. The aglycone of 1, 2 and 4 was determined as siaresinolic acid, which was reported in this genus for the first time. The cytotoxicities of the saponins 1–12, prosapogenins 4a, 5a, 10a–12a and sapogenins siaresinolic acid (SA), oleanolic acid (OA), hederagenin (HE) were evaluated against five human cancer cell lines, including HepG2, HL-60, A549, HeLa and U87MG. The monodesmosidic saponins 6–8, 5a, 10a–12a and sapogenins SA, OA, HE exhibited cytotoxic activity toward all cancer cell lines, with IC₅₀ values ranging from 2.25 to 57.28 μM. Remarkably, the bisdesmosidic saponins 1–4 and 9 showed selective cytotoxicity against the U87MG cells.     

Phytochemical investigation of Millettia dorwardi Coll. et Hemsl

The first phytochemical investigation on the vine stems of Millettia dorwardi Coll. et Hemsl led to the isolation of ten flavonoids (isoafrormosin 1, formononetin 2, afrormosin 3, padmakastein 4, liquiritigenin 5, 4H-1-Benzopyran-4-one,7-hydroxy-5,8-dimethoxy-3-(4-methoxyphenyl)-isoflavone 6, 4H-1-Benzopyran-4-one,7-hydroxy-3-(3-hydroxy-5-methoxyphenyl)-6-methoxy 8, 4H-1-Benzopyran-4-one,6-methoxy-3-(4-methoxyphenyl)-6,4′-dimethoxyisoflavone 9, irisolidone 10, prunetin 11), one heterocycle (5-5′-dibuthoxy-2-2′-bifuran 7) and one new isoflavone glycoside (4H-1-Benzopyran-4-one,5-hydroxymethyl-3-(4-methoxyphenyl)-6-β-d-glucopyranoside-isoflavone 12). Their structures were determined by extensive analysis of their spectroscopic data. Among them, compounds 4, 6–10, 12 were for the first time isolated from this genus. The chemotaxonomic importance of these compounds was also summarized.     

Improved synthesis and the crystal structure of methyl 4,6-dideoxy-4-(3-deoxy- -glycero-tetronamido)-α- -mannopyranoside, the methyl α-glycoside of the intracatenary repeating unit of the O-polysaccharide of Vibrio cholerae O:1

The crude product of deamination of the commercially available -homoserine was acetylated and the 2-O-acetyl-3-deoxy- -glycero-tetronolactone (18) formed was used to N-acylate methyl perosaminide (methyl 4-amino-4,6-dideoxy-α- -mannopyranoside, 12) and its 2,3-O-isopropylidene derivative. The major product isolated from the reaction was the crystalline methyl 4-(4-O-acetyl-3-deoxy- -glycero-tetronamido)-4,6-dideoxy-α- -mannopyranoside (1, 70–75%) resulting from acetyl group migration in the initially formed 2'-O-acetyl derivative. O-Deacetylation of 1 gave the title amide 2. Compound 2, obtained crystalline for the first time, was fully characterized, and its crystal structure was determined. Deoxytetronamido derivatives diastereomeric with 1 and 2, respectively, were obtained by the acylation of 12 with 2-O-acetyl-3-deoxy- -glycero-tetronolactone (prepared from -homoserine), and subsequent deacetylation. Structures of several byproducts of the reaction of 12 with 18 have been deduced from their spectral characteristics. Since these byproducts were various O-acetyl derivatives of 2, the title compound could be obtained in ≈ 90% yield by deacetylating (Zemplén) the crude mixture of N-acylation products, followed by chromatography.     

Dolabellane diterpenoids from Aglaia odorata

Dolabellane diterpenoids, (1R,3E,7E,10S,11S,12R)-dolabella-3,7-dien-10,18-diol (1), (1R,3S,7E,11S,12R)-dolabella-4(16),7-dien-3,18-diol (2), (1R,7E,11S,12R)-18-hydroxydolabella-4(16),7-dien-3-one (3), (1R,3S,4S,7E,11S,12R)-3,4-epoxydolabella-7-en-18-ol (4), and (1R,3R,7E,11S,12R)-dolabella-4(16),7,18-trien-3-ol (5), were obtained from the ornamental plant Aglaia odorata. Their structures were characterized on the basis of spectroscopic analyses and further confirmed by X-ray diffraction. Compounds 1 and 5 showed weak cytotoxicity against the human myeloid leukemia HL-60, hepatocellular carcinoma SMMC-7721, and lung cancer A-549 cells.     

Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12

Matrix metalloproteinase-12 (MMP-12, macrophage elastase) is a member of the MMP family that is responsible for the degradation of extracellular matrix, and is associated with the inflammatory process of chronic obstructive pulmonary disease (COPD). COPD, characterized by progressive and irreversible airflow obstruction, is recently a major cause of mortality and morbidity worldwide. Herein, to develop radioiodinated probes for the early diagnosis of COPD, we designed and synthesized novel MMP-12-targeted dibenzofuran compounds (1–3) with a variety of linker structures (carbamate, amide, and sulfonamide). In competitive enzyme activity assays, it was revealed that the linker structures significantly affected the inhibitory activity against and selectivity for MMP-12. Compound 1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC₅₀?=?8.5?nM) compared to compound 2, with amide linker, and compound 3, with sulfonamide linker. Using bromo-substituted carbamate 13 as a radioiodination precursor, [¹²⁵I]1 was successfully prepared to high radiochemical purity (over 98%) and good specific radioactivity (4.1?GBq/μmol). These results suggest that radioiodinated compound 1 is potent as a novel MMP-12-targeted probe.