Undescribed polyketides from endophytes associated with the critically endangered conifer Abies beshanzuensis.

Four undescribed polyketides, beshanzones A (1) and B (2) as well as beshanhexanols A (3) and B (4), along with three known ones (5-7) were isolated from the rice fermentation of two endophytic fungi associated with the critically endangered Chinese endemic conifer Abies beshanzuensis. γ-Butyrolactone derivatives 1, 2, and 5 were isolated from Phomopsis sp. BSZ-AZ-2, an interesting strain that drawn our attention this time.

"One pot" synthesis of quinazolinone-[2,3]-fused polycyclic scaffolds in a three-step reaction sequence.

Diverse quinazolinone-[2,3]-fused polycyclic skeletons occupy a prominent position in drug discovery. Even with currently available methods there still remain unmet needs for flexible access to such structures. Herein, we have explored a mild "one pot" procedure for the construction of various quinazolinone-[2,3]-fused polycycles.

Construction of indolizine scaffolds from α,ω-alkynoic acids and α,ω-vinylamines sequential-relay catalysis in "one pot".

A simple and efficient method has been developed for the synthesis of a diverse range of aryl-fused indolizin-3-ones through sequential Au(I)-catalyzed hydrocarboxylation, aminolysis, and cyclization, followed by ruthenium-catalyzed ring-closing metathesis. Moderate to good yields were observed with satisfactory substrate scope and functional group tolerance. The developed protocol represents a practical strategy for the construction of bioactive aryl-fused indolizin-3-ones.

Terricoxanthones A-E, unprecedented dihydropyran-containing dimeric xanthones from the endophytic fungus Neurospora terricola HDF-Br-2 associated with the vulnerable conifer Pseudotsuga gaussenii.

An investigation on the secondary metabolites from a rice culture broth of the endophytic fungus Neurospora terricola HDF-Br-2 derived from the vulnerable conifer Pseudotsuga gaussenii led to the isolation and characterization of 34 structurally diverse polyketides (1-34). Seven of them are previously undescribed, including five unprecedented dihydropyran-containing (terricoxanthones A-E, 1-5, resp.) and one rare tetrahydrofuran-containing (terricoxanthone F, 6) dimeric xanthones.

Synthesis, biological evaluation, and molecular modeling of ORM-10921 and its analogs as α -adrenoceptor antagonists.

The α -adrenoceptor (α -AR) is regarded as one of the potential targets for antipsychotics. A few of structurally diverse α -AR antagonists have been reported, among which ORM-10921, containing one rigid tetracyclic framework with two neighboring chiral centers, has exhibited remarkable antipsychotic-like effects and pro-cognitive properties in different animal models. Yet the binding mode of ORM-10921 remains elusive.

Identification and immunological evaluation of novel TLR2 agonists through structural optimization of Diprovocim.

As an important family member of Toll-like receptors (TLRs), TLR2 can recognize various pathogen-associated molecular patterns (PAMPs) such as bacteria and viral components. Accumulating evidence demonstrates that TLR2 agonists play a critical role in cancer immunotherapy and infectious diseases. Diprovocim is the most potent small molecule TLR2 agonist known, showing remarkably immune adjuvant activity in mice.

Synthesis of the analogs of plocabulin and their preliminary structure-activity relationship study.

Plocabulin, a marine natural polyketide isolated from the sponge Lithoplocamia lithistoides, is a novel and potent microtubule-destabilizing agent. Guided by the reported binding mode, several new analogs of plocabulin have been designed through removing the right aliphatic chain and further modifying on the carbamate group and the enamide unit. The preliminary results indicate that the right aliphatic chain in plocabulin is allowed to remove with a little loss of activity, the carbamate group plays a role in the activity, and particularly, the enamide unit has an important effect on the activity.

Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole.

Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole's macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five-nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol.

A fluorine scan on the Zn-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling.

Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a "fluorine scan" strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs.

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A.

Largazole, isolated from a marine of the genus , is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities.

Discovery, synthesis, biological evaluation and molecular docking study of (R)-5-methylmellein and its analogs as selective monoamine oxidase A inhibitors.

(R)-5-Methylmellein (5-MM), the major ingredient in the fermented mycelia of the medicinal fungus Xylaria nigripes (called Wuling Shen in Chinese)¸ was found to be a selective inhibitor against monoamine oxidase A (MAO-A) and might play an important role in the clinical usage of this edible fungus as an anti-depressive traditional Chinese medicine (TCM). Based on the discovery and hypothesis, a variety of (R)-5-MM analogs were synthesized and evaluated in vitro against two monoamine oxidase isoforms (MAO-A and MAO-B). Most synthetic analogs showed selective inhibition of MAO-A with IC values ranging from 0.

CsCO-promoted defluorination and functionalization of α-CF carbonyl compounds in the presence of -, -, and/or -nucleophiles.

A simple, efficient, and mild method for defluorination and functionalization of 3,3,3-trifluoro carbonyl compounds has been developed. In the present method, CsCO can easily convert α-trifluoromethyl esters, amides, and ketones into β,β--, - and/or -substituted α,β-unsaturated carbonyl compounds in the presence of -, -, and -nucleophiles with moderate to excellent yields, and furthermore, this transformation with α-trifluoromethyl ester and a series of 2-aminophenols can result in benzooxazoles in good yields.

The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex.

The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively.

Synthesis of ∆3-2-hydroxybakuchiol analogues and their growth inhibitory activity against rat UMR106 cells.

A series of ∆3-2-hydroxybakuchiol analogues have been synthesized and tested for their growth inhibitory activity against rat UMR106 cells by using the MTT method. Some of them exhibit enhanced activities compared with the natural product, and the preliminary SAR profile shows that the chain tail on the natural product could be subtly modified to enhance the activity and the aromatic moiety or the terminal olefin on the main chain can also be modified without any evident loss of activity. The stereo-configuration of the quaternary chiral center has an important influence on the activity.

Discovery and synthesis of novel luteolin derivatives as DAT agonists.

Luteolin, 5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one, has been proposed and proved to be a novel dopamine transporter (DAT) activator. In order to develop this potential of luteolin, a series of novel luteolin derivatives were designed, synthesized, and evaluated for their DAT agonistic activities, utilizing constructed Chinese hamster ovary (CHO) cell lines stably expressing rat DAT. Biological screening results demonstrated that luteolin derivatives 1d, 1e, and 4c carry great DAT agonistic potency (EC(50)=0.

First stereospecific synthesis of (E)- or (Z)-alpha-fluoroenones via a kinetically controlled Negishi coupling reaction.

A highly stereospecific synthesis of (E)- or (Z)-alpha-fluoro-alpha,beta-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 degrees C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields).

A novel diastereoselective synthesis of (Z)-fluoroalkenes via a Nozaki-Hiyama-Kishi-type reaction.

A highly diastereoselective and straightforward synthesis for (Z)-2-fluoroallylic alcohols via a Nozaki-Hiyama-Kishi-type reaction with the corresponding bromofluoroolefins was developed, providing an easy access to highly interesting fluorinated synthons.

A facile and mild method for the synthesis of terminal bromofluoroolefins via diethylzinc-promoted Wittig reaction.

[reaction: see text] Synthesis of 1-bromo-1-fluoroolefins was achieved in good yields via a Wittig reaction promoted by diethylzinc, even with nonactivated aldehydes and ketones as starting materials.