Metal- and photocatalyst-free approach to visible-light-induced acylation of quinoxalinones.

A transition-metal- and photocatalyst-free photochemical reaction was successfully developed for the direct acylation of quinoxalin-2(1H)-ones, which was enabled by the formation of electron donor-acceptor (EDA) complexes. The use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the electron donor allows efficient and operationally simple access to a series of C3-aroylated and acylated quinoxalin-2(1H)-ones with moderate to good yields.

Base-Mediated and Silver-Catalyzed Divergent Synthesis of Hydroxynaphthalenamides and Phosphorylated Dihydronaphthylamides from Enone-Oxazolones.

An efficient divergent approach to functionalized naphthalene derivatives, the naphthalenamides, via base-mediated and silver-catalyzed cyclization has been developed using enone-oxazolones as the precursors. This protocol utilized base in methanol with heating to construct the corresponding hydroxynaphthalenamides 2 by a C-C bond formation, oxazolone ring-opening, and aromatization in good yields. On the other hand, phosphorylated dihydronaphthylamides 3 were generated by using H-phosphonate as the phosphonating reagent in a silver-catalyzed cyclization involving the phospha-1,4-addition/intramolecular ring closure with concomitant C-P/C-C bond formation in good yields.

Two new serratene triterpenes from club moss cultivars.

Two new serratene triterpenes, 14α,21ß-dihydroxyserrat-3ß-yl acetate and 3α,21ß-dihydroxyserrat-14-en-23-oic acid, together with eight known compounds were isolated from two club moss cultivars, Phlegmariurus carinatus (Desv.) Ching and Phlegmariurus nummulariifolius (Blume) Ching. 14α,21ß-Ddihydroxyserrat-3ß-yl acetate (1) was isolated from P. carinatus, and 3α,21ß-dihydroxyserrat-14-en-23-oic acid (2), an undescribed carboxylic group at C-23 position of the serratene triterpenoids, was isolated from P. nummulariifolius. The structures of these new compounds were elucidated by using HR-ESIMS, UV, IR, 1D (1H and 13C NMR spectra), 2D NMR spectra, experimental ECD spectrometry and the single-crystal X-ray analysis. Biological evaluation of 14α,21ß-dihydroxyserrat-3ß-yl acetate (1) and lycoclavanol (8) revealed moderate cytotoxic activity on three tumor cell lines (HepG2, A549 and HuCCA-1) whereas 3α,21ß-dihydroxyserrat-14-en-23-oic acid (2) showed strong inhibitory effect on HuCCA-1 cells with the IC50 of 4.72 µM.

Phlegcarines A-C, three Lycopodium alkaloids from Phlegmariurus carinatus (Desv. ex Poir.) Ching.

Three undescribed Lycopodium alkaloids, phlegcarines A-C, along with nine known alkaloids, were isolated from the aerial parts of a gardening clubmoss Phlegmariurus carinatus (Desv. ex Poir.) Ching. Phlegcarine A is an undescribed Lycopodium alkaloid possessing an unprecedented 5/9/6/6 fused-tetracyclic ring system consisting of an oxa-cyclononanone, a piperidine, a methylcyclohaxane and an oxazolidine. Phlegcarine B is the first N-chloromethyl piperidinium Lycopodium alkaloid of (+)-lycoflexine. The semi-synthesis of phlegcarine B was investigated from (+)-fawcettimine. Phlegcarine C, an undescribed epimer of 12-epilycodoline, is a rare lycopodine-type alkaloid with ß-oriented H-4. Transformation of phlegcarine C and lycodoline to 12-epilycopodine N-oxide via keto-enol tautomerization was investigated using m-CPBA. The structural assignments were established through comprehensive spectroscopic techniques and chemical correlations. Phlegcarines A-C were assayed for their anti-acetylcholinesterase activity, but none of them exhibited biological activity more potent than that of huperzine A.

Siamenflavones A-C, three undescribed biflavonoids from Selaginella siamensis Hieron. and biflavonoids from spike mosses as EGFR inhibitor.

Three undescribed biflavonoids (BFVs), siamenflavones A-C along with twelve BFVs were isolated from Selaginella siamensis Hieron. and Selaginella bryopteris (L.) Baker (Selaginellaceae). The chemical structures of undescribed compounds were established through comprehensive spectroscopic techniques, chemical correlations, and X-ray crystallography. The ten isolated BFVs, siamenflavones A-C, delicaflavone, chrysocauflavone, robustaflavone, robustaflavone-4-methylether, amentoflavone, tetrahydro-amentoflavone, and sciadopitysin were evaluated for the antiproliferative effects against four human cancer cell lines A549, H1975, HepG2 and T47D. Delicaflavone and robustaflavone 4'-methylether exerted strong effects on the four human cancer cell lines. Siamenflavone B, delicaflavone and robustaflavone 4'-methylether showed potent inhibitory activities against wild-type EGFR. The inhibition of the compounds was further supported by molecular docking and predictive intermolecular interactions. Molecular dynamics simulation studies of siamenflavone B and robustaflavone-4'-methylether complexed to EGFR-TK further supported inhibition of the compounds to the ATP binding site. Finally, analysis of pharmacokinetic and electronic properties using density-functional theory and known drug index calculations suggest that the compounds are pharmaceutically compatible for drug administration.

Two new nor-lignans, siamensinols A and B, from Selaginella siamensis Hieron. and their biological activities.

Two new nor-lignans siamensinols A-B (1-2) and seven known compounds agatharesinol (3), syringaresinol-glucoside (4), noreugenin (5), 8-methyleugenitol (6), melachromone (7), uncinoside A (8) and daucosterol (9) were isolated from Selaginella siamensis Hieron. The structures of the new compounds were elucidated on the basis of comprehensive spectroscopic methods, including 1 D, 2 D-NMR, HR-ESI-MS and CD spectrometry. Compounds 1-2 showed moderate inhibitory effect on MOLT-3 cells while 8-methyleugenitol (6) exhibited moderate inhibitory effect on three tumor cells (HepG2, A549 and HuCCA-1). Compounds 2-3 showed the potent cancer chemoprevention in DPPH, XXO, IXO and AIA assays.

In Silico-Guided Rational Drug Design and Semi-synthesis of C(2)-Functionalized Huperzine A Derivatives as Acetylcholinesterase Inhibitors.

Huperzine A (1, Hup A), a lycodine-type Lycopodium alkaloid isolated from Thai clubmosses Huperzia squarrosa (G. Forst.) Trevis., H. carinata (Desv. ex. Poir.) Trevis., H. phlegmaria (L.), and Phlegmariurus nummulariifolius (Blume) Chambers (Lycopodiaceae), exerts inhibitory activity on acetylcholinesterase, a known target for Alzheimer's disease therapy. This study investigated the structure-activity relationship of C(2)-functionalized and O- or N-methyl-substituted huperzine A derivatives. In silico-guided screening was performed to search for potential active compounds. Molecular docking analysis suggested that substitution at the C(2) position of Hup A with small functional groups could enhance binding affinity with AChE. Consequently, 12 C(2)-functionalized and four O- or N-methyl-substituted compounds were semi-synthesized and evaluated for their eeAChE and eqBChE inhibitory activities. The result showed that 2-methoxyhuperzine A (10) displayed moderate to high eeAChE inhibitory potency (IC50 = 0.16 µM) with the best selectivity over eqBChE (selectivity index = 3633). Notably, this work showed a case of which computational analysis could be utilized as a tool to rationally screen and design promising drug molecules, getting rid of impotent molecules before going more deeply on labor-intensive and time-consuming drug discovery and development processes.

Highly Regioselective Tandem Reaction of Ene-Yne-Oxazolones Induced by H-Phosphonates: Construction of Phosphinylindane Derivatives.

A highly regioselective divergent approach for the phosphine-containing indane/indene derivatives from the ene-yne-oxazolone precursors was reported. An insight into the reaction mechanism involving the phospha-1,4-addition followed by 5-exo-dig ring closure with a concomitant C-P/C-C bond formation was also proposed. This promising protocol utilized H-phosphonate as the phosphonating reagent in a silver-catalyzed or base-mediated cascade cyclization to construct the corresponding phosphorylated spiroindenoxazolones and amidoindenes, respectively, in good yields (up to 88% yield).

Serratene triterpenoids and their biological activities from Lycopodiaceae plants.

The plants of Lycopodiaceae family, distributed across China, India and also Southeast Asia, have been used as folk medicines. The phytochemical constitutent studies of this family was widely reported. Serratene trierpenoids is one of phytochemical constitutent type, which have been mainly isolated from this plant family. To date, more than 100 serratene-type triterpenoids have been reported and several of them have been shown promising biological activities, especially cytotoxicity and chemopreventive activity. This review covers the structural classification, biological activities and hypotheses about biosynthetic pathways of serratene-type triterpenes.

Three Lycopodium alkaloids from Thai club mosses.

Phytochemical constituents in alkaloid extracts from three Thai club mosses Huperzia squarrosa, Huperzia phlegmaria and Phlegmariurus nummularifolius were investigated. Squarrosinoxide was an undescribed Lycopodium alkaloid from H. squarrosa possessing an unprecedented 6/5/7 tricyclic spiro system. Acetyllycophlegmarianol was an undescribed N-oxide lycopodine-type alkaloid isolated from H. phlegmaria. 4-Epilycopodine, an undescribed epimer of lycopodine, was first isolated from P. nummularifolius. The structural assignments were established through comprehensive spectroscopic techniques and chemical correlations. All compounds were assayed for their anti-acetylcholinesterase activity in vitro.

Base-Mediated Cascade Cyclization: Stereoselective Synthesis of Benzooxazocinone.

A new strategy for the synthesis of the oxa-azabicyclo[3.3.1]nonane subunit, a component of the naucleamide E core structure, has been developed. This annulation reaction between 1-substituted 3,4-dihydroisoquinolines and coumarin derivatives conveniently affords the oxa-azabicyclo[3.3.1]nonane framework via a base-mediated cascade cyclization under aqueous conditions. The value of this work lies in the efficient formation of the oxa-azabicyclo[3.3.1]nonane skeleton via a process whereby all the C-C, C-O, and C-N bond formations occur in a single chemical operation. In addition, the subsequent ring opening of these compounds furnished pyridoisoquinoline derivatives.

Squarrosine A and Pyrrolhuperzine A, New Lycopodium Alkaloids from Thai and Philippine Huperzia squarrosa.

Two new Lycopodium alkaloids, squarrosine A (1) and pyrrolhuperzine A (2), were isolated from the Thai and Philippine plant Huperzia squarrosa. (R)-2-Piperidineacetic acid (5) was a known alkaloid, but has now been isolated for the first time from a natural source. Their structures were elucidated using extensive spectroscopic analyses and, for pyrrolhuperzine A (2), confirmation by chemical transformation. The new compounds exhibited moderate acetylcholinesterase inhibitory activities.

Lycophlegmariols A-D: cytotoxic serratene triterpenoids from the club moss Lycopodium phlegmaria L.

Lycopodium serratene triterpenoids, along with an abietane-type diterpene were isolated from the methanol extract of club moss Lycopodium phlegmaria L. The structures of these hitherto unknown lycopodium terpenoids were elucidated on the basis of spectroscopic analysis. Pentacyclic triterpenoids, 21ß-hydroxy-serrat-14-en-3α-ol (1) and 21ß-hydroxy-serrat-14-en-3α-yl acetate (2) were isolated together with four serratene triterpeneoids established as 21ß,29-dihydroxyserrat-14-en-3α-yl dihydrocaffeate (lycophlegmariol A, 5), 21ß,24,29-trihydroxyserrat-14-en-3ß-yl dihydrocaffeate (lycophlegmariol B, 6), 21α,24-dihydroxyserrat-14-en-3ß-yl 4-hydroxycinnamate (lycophlegmariol C, 7), and 14ß,21α,29-trihydroxyserratan-3ß-yl dihydrocaffeate (lycophlegmariol D, 8) as well as a known lycophlegmarin (9). An abietane-type diterpene, 8,11,13-abietatriene-3ß,12-dihydroxy-7-one (margocilin, 10), was isolated for the first time from a Lycopodium plant. Lycophlegmariol B (6), D (8) and compound 1 showed inhibitory effects against MOLT-3 acute lymphoblastic leukemia (T-lymphoblast) with IC(50) of 14.7, 3.0 and 2.9 µM, respectively.

Stereocontrolled synthesis of an indole moiety of sespendole and stereochemical assignment of the side chain.

Two possible diastereomers of the indole moiety of sespendole were synthesized from 3-hydroxy-4-nitrobenzaldehyde in a highly stereoselective manner. Comparison of (1)H and (13)C NMR spectra of the two synthetic materials with those sespendole leads us to propose that the relative stereochemistry of the epoxyalcohol is syn.

Overcoming multidrug resistance in human lung cancer with novel benzo[a]quinolizin-4-ones.

AIM: To investigate the ability of synthetic benzo[a]quinolizin-4-one derivatives to reverse multidrug resistance (MDR) in lung cancer cells. MATERIALS AND METHODS: A cell line with MDR, A549RT-eto, was established by exposure to 1.5 µM etoposide. Cytotoxic activity was assayed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromine (MTT) method. The mechanism of drug resistance was studied by real-time PCR, Western blot analysis, and flow cytometry. Benzo[a]quinolizin-4-one derivatives were synthesized and tested for cytotoxic activity and ability to modulate MDR. RESULTS: A549RT-eto cells had an IC(50) for etoposide of 176 µM, 28-fold higher than parental cells, due to increased levels of MDR1 gene and P-glycoprotein (P-gp), resulting in greater drug efflux. Three benzo[a]quinolizin-4-ones reduced etoposide IC(50) from 176 µM to 22.4 µM -24.7 µM. This resulted from increased drug accumulation without altering P-gp expression at the transcription or translation level. CONCLUSION: Non-toxic concentrations of benzo[a]quinolizin-4-one derivatives can reverse drug resistance of A549RT-eto by increasing the intracellular drug accumulation.

Synthesis and biological activities of azalamellarins.

The synthesis of azalamellarins, a new series of lactam analogues of biologically active lamellarins, was achieved using Cu(I)-mediated and microwave-assisted C-N(amide) bond formation. Seventeen azalamellarins, including N-allylazalamellarins and N-propylazalamellarins chi-D, L-N, and J-dehydro J, were synthesized and evaluated for their cytotoxicity against the cancer cell lines HuCCA-1, A-549, HepG2, and MOLT-3. The results showed that certain azalamellarins exhibited good activities in the micromolar IC(50) value range (IC(50)=the drug concentration that causes 50 % of cell-growth inhibition after 72 h of continuous exposure to the test molecule), comparable to their parent lamellarin analogue.

Bacillus subtilis SSE4 produces subtulene A, a new lipopeptide antibiotic possessing an unusual C15 unsaturated beta-amino acid.

Subtulene A, a new cyclic lipopeptide, was isolated from the culture broth of Bacillus subtilis SSE4. This antibiotic compound contained the seven common alpha-amino acids, L-Asn-1, D-Tyr-2, D-Asn-3, L-Gln-4, L-Pro-5, D-Asn-6, L-Ser-7 and the unique beta-amino acid-8 present in the iturin family. 1D and 2D NMR, as well as MS analyses, identified the beta-amino acid as 3-amino-13-methyltetradec-8-enoic acid, an Iso C15 long chain beta-amino acid. B. subtilis SSE4 was also found to produce iturin A. B. subtilis SSE4 culture filtrate exhibited both antifungal and antibacterial activities.

Synthesis of unsymmetrical benzil licoagrodione.

A synthesis of unsymmetrical 1,2-diarylethane-1,2-dione is reported involving the intramolecular cyclization of anionic benzylic ester of the aryl benzyl ether followed by oxidation employing dioxirane. With the use of microwave irradiation, licoagrodione was prepared from Claisen rearrangement of the corresponding allyl phenyl ether 1,2-diketone readily available from the Lindlar's reduction of the corresponding alkyne derivative. Subsequent removal of protecting groups then furnished the desired product.