Chlorahololides A and B, two potent and selective blockers of the potassium channel isolated from Chloranthus holostegius

[structure: see text] Chlorahololides A(1) and B(2), two highly complex sesquiterpenoid dimers, were isolated from Chloranthus holostegius. Their structures and absolute configurations were established by NMR spectroscopy, X-ray crystallography, and CD. Chlorahololides A (1) and B (2) exhibited potent and selective inhibition on the delayed rectifier (IK) K+ current, with an IC50 of 10.9 and 18.6 microM, respectively.     

Synthesis of hexacyclic parnafungin A and C models

A convergent, practical route to unstable hexacyclic parnafungin A and C models has been developed. Two iodoxanthones were prepared in four or five steps (33-50% overall yield). Suzuki-Miyaura coupling of the iodoxanthones with excess readily available 3-carbomethoxy-2-nitrophenyl pinacol boronate afforded the hindered highly functionalized 2-arylxanthones (53-58%) in the first key step. In the second key step, zinc reduction gave benzisoxazolinones that were treated with MsCl and then base to generate the unstable hexacyclic parnafungin A (13% overall yield for 8 steps) and C (8% overall yield for 9 steps) models. Analogously to the parnafungins, hexacyclic parnafungin C model decomposes to a phenanthridine with a half-life of 2 d in CDCl(3).     

Scalable synthesis of cortistatin A and related structures

Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective Δ(16)-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, Δ(16)-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.     

A formal synthesis of (-)-mycalamide A

Novel strategies are developed for an efficient formal synthesis of (-)-mycalamide A. The left-hand side (-)-7-benzoylpederic acid is synthesized from (2S,3S)-2,3-epoxybutane. The key features include a highly regioselective Ru-catalyzed alkene-alkyne coupling reaction and a novel way to control the challenging C(7) stereocenter. The right-hand side was synthesized from (R)-pantolactone. The complex trioxodecalin core is constructed with two Pd(0)-catalyzed O-pi-allyl cyclizations. The first one is chemoselective, while the second one is highly diastereoselective. Three additional steps would be required to complete a total synthesis of (-)-mycalamide A.     

Total synthesis of +-superstolide A

A convergent and highly stereocontrolled synthesis of +-superstolide A (1) has been accomplished. Key steps of this synthesis include the intramolecular Suzuki reaction of 26 and the highly diastereoselective transannular Diels-Alder cyclization of macrocyclic octaene 3.     

Total syntheses of angelicoin A, hericenone J, and hericenol A via migratory prenyl- and geranylation-aromatization sequences

A five-step synthesis of the natural product angelicoin A using a late stage highly regioselective palladium(0)-catalyzed decarboxylative prenyl migration and aromatization sequence as the key step is reported. The method was extended with geranyl migration in eight-step total syntheses of hericenone J and hericenol A from geraniol.     

Chukrasones A and B: Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis

Two new limonoids, chukrasone A (1) incorporating a highly rearranged A/B ring system and chukrasone B (2) possessing the first 16,19-dinor limonoid backbone with an extended C3 unit at C-15, were isolated from Chukrasia tabularis. Their structures were characterized on the basis of detailed spectroscopic analysis. Compounds 1 and 2 exhibited potential inhibition of the delayed rectifier (I(K)) K(+) current.     

A domino desulfitative coupling and decarboxylative coupling of 3, 4-dihydropyrimidine-2-thiones with copper(I) carboxylates

A novel and general carbon-nitrogen and carbon-carbon cross-coupling reaction between 3,4-dihydropyrimidine-2-thiones and copper(I) carboxylates were performed in the presence of palladium acetate. The copper(I) carboxylates act not only as desulfurative reagents but also as sources of carbon nucleophiles. A wide array of highly substituted and functionalized pyrimidines scaffolds were synthesized in good yields.     

Arnequinol A and arnequinone A,two unique meroterpenoids from Arnebia euchroma

Arnequinol A(1), featuring an unprecedented 6/6/3 tricyclic carbon skeleton fused with a heptatomic oxo-bridge, together with arnequinone A(2) bearing a highly conjugated methyl-shifting benzogeijerene skeleton, were isolated from Arnebia euchroma. Their structures were elucidated by extensive spectroscopic methods and quantum chemical calculations of the13C nuclear magnetic resonance(NMR) data and electronic circular dichroism(ECD) spectra. The plausible biosynthetic pathways for 1 and 2 were p...     

3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists

Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.     

Spermine binding to Parkinson's protein alpha-synuclein and its disease-related A30P and A53T mutants

Aggregation of alpha-synuclein (alpha-syn), a protein implicated in Parkinson's disease (PD), is believed to progress through formation of a partially folded intermediate. Using nanoelectrospray ionization (nano-ESI) mass spectrometry combined with ion mobility measurements we found evidence for a highly compact partially folded family of structures for alpha-syn and its disease-related A53T mutant with net charges of -6, -7, and -8. For the other early onset PD mutant, A30P, this highly compact population was only evident when the protein had a net charge of -6. When bound to spermine near physiologic pH, all three proteins underwent a charge reduction from the favored solution charge state of -10 to a net charge of -6. This charge reduction is accompanied by a dramatic size reduction of about a factor of 2 (cross section of 2600 A2 (-10 charge state) down to 1430 A2 (-6 charge state)). We conclude that spermine increases the aggregation rate of alpha-syn by inducing a collapsed conformation, which then proceeds to form aggregates.     

Total synthesis of (+)-superstolide A

A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired cycloadduct with lower stereoselectivity (6:1:1).     

Total Synthesis of Aspercyclides A and B via Intramolecular Oxidative Diaryl Ether Formation

A highly efficient total synthesis of the 11-membered cyclic aspercyclides A (1) and B (2) has been achieved by chemo- and regioselective intramolecular oxidative C-O bond formation from differently substituted diphenols.     

A single-strand conformation polymorphism method by capillary electrophoresis with laser-induced fluorescence for detection of the T1151A mutation in hMLH1 gene

Mutation of hMLH1 gene plays an important role in human tumorigenesis. A highly sensitive single-strand conformation polymorphism (SSCP) method for detection of the T1151A mutation in exon 12 of the hMLH1 gene was for the first time developed employing laser-induced fluorescence capillary electrophoresis (LIF-CE). Effects of the concentration of linear polyacrylamide solution, running temperature, running voltage and the addition of glycerol on SSCP analysis were investigated, and the optimum separation conditions were defined. Thirty colorectal cancer patients and eight lung cancer patients were screened and the T1151A mutation was found in four of them. Based on CE-sequencing the mutation was further confirmed. To our knowledge, this is for the first time that the T1151A mutation is found in lung cancer. Our method is simple, rapid, and highly sensitive and is well suited to the analysis of large numbers of clinical samples.     

A sensitive probe for the detection of Zn(II) by time-resolved fluorescence

A new, highly sensitive fluorescent sensor for Zn(II) ion (a tris(2-pyridylmethyl)amine derivative) shows very strong binding and Zn(II) concentration-dependent biexponential time-resolved fluorescence (TRF) decay profiles that can be used for ratiometric estimates of Zn(II) concentrations. The ligand-metal complexes were characterized in solution by spectroscopic techniques and in the solid state by X-ray crystallography. The TRF studies revealed that the sensor aggregates in the absence of Zn(II) in a ligand concentration-dependent manner, a complication that is discerned by TRF but not by steady-state fluorescence ratiometric sensing techniques. It is shown that the same TRF methods are highly useful for monitoring Zn(II) concentrations in A549 epithelial lung cells in vitro and that the results were consistent with those in solution.     

A simple and efficient preparation of deoxynucleoside phosphoramidites in situ

A highly selective activation of bis-(pyrrolidino) methoxyphosphine by 4,5-dichloroimidazole has been developed and successfully used in the preparation of deoxynucleoside phosphoramidites.     

Structure and properties of an hybrid system based on bisphenol A polycarbonate modified by A polyamide 6/organoclay nanocomposite

Blends of poly(carbonate of bisphenol A) (PC) with minute amounts of a nanocomposite based in polyamide 6 (PA6) with a layered organoclay (nPA6) were obtained upon melt mixing by varying the contents of both nPA6 and organoclay. The ternary nanocomposites (NC) were composed of a PC-rich matrix with some mixed PA6 present, and by a neat nPA6 dispersed phase. Upon dissolution of the matrix of the NC’s, the dispersed phase showed a highly fibrillar morphology that resembled that of thermoplastic/liquid crystalline polymer (LCP) blends. The cryogenically fractured surfaces observed by SEM showed a very fine particle size that was attributed to the presence of PA6 in the matrix and indicated a low interfacial tension. The Young’s modulus behaviour is proposed to be a consequence of the slight orientation of the PC-rich matrix and the highly fibrillated and oriented nPA6 dispersed phase. The important reinforcement effect of the dispersed phase is attributed to the additive effects of its large degree of orientation, and the reinforcing effect of the organoclay.     

Total synthesis and initial structure-function analysis of the potent V-ATPase inhibitors salicylihalamide A and related compounds

Salicylihalamide A is the first member of a growing class of macrocyclic salicylate natural products that induce a variety of interesting phenotypes in cultured mammalian cells. Salicylihalamide A was reported to be a unique and highly differential cytotoxin and a potent inhibitor of the mammalian vacuolar (H(+))-ATPase. The total synthesis of both enantiomers of salicylihalamide A, a revision of the absolute configuration assigned to the natural product, and extensive structure-function studies with synthetic salicylihalamide variants are reported. These studies were possible only due to a highly efficient synthetic strategy that features (1) a remarkably E-selective ring-closing olefin metathesis to construct the 12-membered benzolactone skeleton 29, (2) a mild stereocontrolled elaboration to E-alkenyl isocyanate 41, and (3) addition of carbon, oxygen, and sulfur nucleophiles to isocyanate 41 to obtain salicylihalamide A and congeners. We demonstrate for the first time that salicylihalamide A is a potent inhibitor of fully purified reconstituted V-ATPase from bovine brain, and have identified several similarly potent side chain modified derivatives, including salicylihalamide dimers 43-45. In combination, these studies have laid the foundation for ongoing studies aimed at a comprehensive understanding of salicylihalamide's mode-of-action, of potential relevance to the development of lead compounds for the treatment of osteoporosis and cancer.     

A Highly Active System for the Metal‐Free Aerobic Photocyanation of Tertiary Amines with Visible Light: Application to the Synthesis of Tetraponerines and Crispine A

A highly efficient metal‐free catalytic system for the aerobic photocyanation of tertiary amines with visible light is reported. The use of air as terminal oxidant offers an improved safety profile compared with pure oxygen, the used compact fluorescent lamp (CFL) light sources are highly economical, and no halogenated solvents are required. This system not only proves to be effective for a wide variety of trialkylamines, pharmaceuticals, and alkaloids but remarkably also allows the lowest catalyst loading (0.00001 mol % or 0.1 ppm) ever reported for an organic dye. Bruylants reactions and C‐alkylation/decyanations were performed on the obtained α‐aminonitriles to demonstrate the postfunctionalization of complex molecules. The catalytic system is furthermore applied in the short and effective syntheses of the alkaloids (±)‐crispine A and the tetraponerines T7 and T8.     

Synthesis of bistramide A

We have developed an efficient and highly stereocontrolled synthesis of bistramide A, a selective activator of protein kinase C isotype delta. Our synthetic strategy featured a novel bidirectional approach for spiroketal construction based on the ring-opening/cross-metathesis sequence employing a highly strained cyclopropenone acetal. The synthesis afforded the final target with the longest linear sequence of 15 steps and provided unambiguous structural determination of bistramide A, including assignment of the previously unknown C(37) stereochemistry.