Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of... more
Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC(50) of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2', and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.
Research Interests: Chemistry, Organic Chemistry, Evaluation, Enzyme Inhibitors, Medicine, and 15 moreHumans, Natural Product, Stereochemistry, Methylene Blue, Tryptophan, Neurotransmitters, Structure activity Relationship, Protein Binding, Chemical Synthesis, Indole Alkaloids, Monoamine oxidase, Potency, Selectivity, Pharmacology and pharmaceutical sciences, and Monoamine oxidase inhibitors
Research Interests: Natural Products, Biology, China, Pharmacognosy, Medicine, and 14 moreStructural Analysis, Macromolecular X-Ray Crystallography, Biological Sciences, CHEMICAL SCIENCES, Chine, Isolation, Absolute Configuration, Diterpenes, Molecular Conformation, Molecular Structure, Plant Leaves, Terpenoid, Plant Leaf, and Medical and Health Sciences
Research Interests: Chemistry, Complementary and Alternative Medicine, Plant Biology, Pharmacognosy, Medicine, and 13 moreMacromolecular X-Ray Crystallography, Crystal structure, Humans, Asteraceae, High Pressure Liquid Chromatography, Anti-Bacterial Agents, Plant extracts, Antifungal Agents, Microbial Sensitivity Tests, Crystalline Structure, Lactones, Terpenoid, and Pharmacology and pharmaceutical sciences
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ABSTRACT Studies on methoxylation in the 7H-naphtho[1,2,3-i,j][2,7]naphthyridin-7-one (sampangine) system represented by 3-bromo- and 4-bromosampangine as well as sampangine itself are described. We have found that regioselectivity of... more
ABSTRACT Studies on methoxylation in the 7H-naphtho[1,2,3-i,j][2,7]naphthyridin-7-one (sampangine) system represented by 3-bromo- and 4-bromosampangine as well as sampangine itself are described. We have found that regioselectivity of nucleophilic substitution in the sampangine system can be directed by reaction conditions. Under kinetic control (lower temperatures) substitution at C-4 is the predominant reaction, regardless of whether 3-bromo or 4-bromosampangine were used. At higher temperatures, when the reaction is thermodynamically controlled, substitution of the bromine atom at C-3 predominates. This is the first reported example of nucleophilic substitution in ring A of the 7H-naphtho [1,2,3-i,j][2,7]naphthyridin-7-one system.
The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are... more
The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G pro...
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ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select... more
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to... more
CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ(7)steroids in Smith-Lemli-Opit...
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Research Interests: Catalysis, Kinetics, Mass Spectrometry, Mitochondria, Magnetic Resonance Spectroscopy, and 19 moreWestern blotting, Cell line, Humans, Placenta, Mice, Animals, Male, Skin, High Performance Liquid Chromatography, High Pressure Liquid Chromatography, Cattle, European, Rats, Time Factors, Gas Chromatography/mass Spectrometry, Quntitative Thin Layer Chromatography, Human Fibroblasts, Pregnenolone, and Biochemistry and cell biology
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... The authors would like to acknowledge Ms. Kelly Thomas for her help during experiments with microbes, Ms. Anna Kochanowska for recording mass spectra, Dr. Jiangnan Peng for 600 MHz NMR of salvinorin B, and Dr. Asok ... Chartoff EH,... more
... The authors would like to acknowledge Ms. Kelly Thomas for her help during experiments with microbes, Ms. Anna Kochanowska for recording mass spectra, Dr. Jiangnan Peng for 600 MHz NMR of salvinorin B, and Dr. Asok ... Chartoff EH, Potter D, Damez-Werno D, Cohen BM ...
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Research Interests: Inflammation, Drug interactions, Mice, Animals, Male, and 14 moreAcetylcholine, Hallucinogens, Synaptic Transmission, Clinical Sciences, Enteric Nervous System, Plant extracts, Diterpenes, Salvia, Gastrointestinal motility, Muscle contraction, Active Ingredient, Neurosciences, Ileum, and Plant Leaves
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The natural cembranolide sarcophine (3) and its lactone ring-opened analogue (10) were oxidized using selenium dioxide under different reaction temperatures to prepare hydroxylated derivatives. Nine new compounds were obtained, six of... more
The natural cembranolide sarcophine (3) and its lactone ring-opened analogue (10) were oxidized using selenium dioxide under different reaction temperatures to prepare hydroxylated derivatives. Nine new compounds were obtained, six of them targeted hydroxylated derivatives. The determination of regio- and stereochemistry as well as the mechanistic considerations on the selectivity observed in these reactions are discussed on the basis of 2D NMR and molecular modeling. In preliminary in vitro tests on inhibition of EBV-EA activation, compounds 10 and 12-15 have shown higher activity than the known chemopreventive agent sarcophytol A.
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Ten new labdane diterpenoids, lagopsins A-H (1-3, 5, 7-10) and 15-epi-lagopsins C and D (4, 6), together with five known labdane diterpenoids (11-15), were isolated from the whole plants of Lagopsis supina. The absolute configuration of... more
Ten new labdane diterpenoids, lagopsins A-H (1-3, 5, 7-10) and 15-epi-lagopsins C and D (4, 6), together with five known labdane diterpenoids (11-15), were isolated from the whole plants of Lagopsis supina. The absolute configuration of lagopsin A (1) was determined by single-crystal X-ray crystallographic analysis. Compounds 7, 9, 13, and 15 exhibited moderate inhibition of nitric oxide production stimulated by lipopolysaccharide in BV-2 microglial cells with IC50 values in the range 14.9-34.9 μM.
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Several A- and B-ring-substituted sampangines were synthesized and evaluated for antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens. Electrophilic halogenation provided a channel for... more
Several A- and B-ring-substituted sampangines were synthesized and evaluated for antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens. Electrophilic halogenation provided a channel for structural elaboration of the sampangine B-ring at position 4, while the synthesis of A-ring 3-substituted sampangines and benzo[4,5]sampangine (24) were achieved from the corresponding functionalized cleistopholines. Two-dimensional NMR spectroscopy was used to rigorously characterize the A- and B-ring substituent patterns. Structure-activity relationship studies revealed the activity of the sampangines was enhanced by the presence of a substituent at position 3 or by a 4,5-benzo group.
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ABSTRACT Studies on methoxylation in the 7H-naphtho[1,2,3-i,j][2,7]naphthyridin-7-one (sampangine) system represented by 3-bromo- and 4-bromosampangine as well as sampangine itself are described. We have found that regioselectivity of... more
ABSTRACT Studies on methoxylation in the 7H-naphtho[1,2,3-i,j][2,7]naphthyridin-7-one (sampangine) system represented by 3-bromo- and 4-bromosampangine as well as sampangine itself are described. We have found that regioselectivity of nucleophilic substitution in the sampangine system can be directed by reaction conditions. Under kinetic control (lower temperatures) substitution at C-4 is the predominant reaction, regardless of whether 3-bromo or 4-bromosampangine were used. At higher temperatures, when the reaction is thermodynamically controlled, substitution of the bromine atom at C-3 predominates. This is the first reported example of nucleophilic substitution in ring A of the 7H-naphtho[1,2,3-i,j][2,7]naphthyridin-7-one system.
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Amino- and urea-substituted thiazoles exhibited in vivo herbicidal activity on duckweed (Lemna paucicostata Hegelm. strain 6746) cultures and appeared to act via inhibition of photosynthetic electron transport system. A small number of... more
Amino- and urea-substituted thiazoles exhibited in vivo herbicidal activity on duckweed (Lemna paucicostata Hegelm. strain 6746) cultures and appeared to act via inhibition of photosynthetic electron transport system. A small number of the thiazole derivatives tested were active but only at relatively high concentrations. The most active structures were the amino-substituted thiazoles with isopropyl and n-butyl side chains and the urea-substituted thiazole with p-chlorophenyl side chain. Decreasing the length of the side chain had a negative effect on the PSII inhibitory activity. The urea-substituted series was as a group less active than the amino series, and the free acid series had no biological activity. The most active compounds competed for the same binding site as atrazine on PSII. Computer modeling highlighted the structural similarities between some of the thiazoles and the commercial herbicides diuron and atrazine.
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Salvinorin A ((2S,4aR,6aR,7R,9S,10aS, 10bR)-2H-naphtho[2,1-c]pyran-7-carboxylic acid, 9-(acetyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo methyl ester, 1, CAS 83729-01-5) has been shown to bind with high affinity and... more
Salvinorin A ((2S,4aR,6aR,7R,9S,10aS, 10bR)-2H-naphtho[2,1-c]pyran-7-carboxylic acid, 9-(acetyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo methyl ester, 1, CAS 83729-01-5) has been shown to bind with high affinity and selectivity to the kappa-opioid receptor (KOR) as an agonist. Bioisosteres of 1 were developed and biologically evaluated in binding and functional assays. The C-2 thioacetate isoster produced comparable activity to 1, but nitrogen substitution had a diminishing effect. Intermediates, which lack a beta-carbonyl at C-2, displayed moderate affinity. The derivatives were tested against all opioid subtypes and were selective towards KOR.