Project description:Hexacyclic congeners 3 and 4 of palau'amine, which incorporate both guanidine functional groups and have the cis configuration of the azabicyclo[3.3.0]octane core, are prepared in 14 steps from cycloadduct 6. Synthetic access to these analogues allows the first direct comparison of NMR data for hexacyclic diguanidine structures having the originally proposed cis-azabicyclo[3.3.0]octane fragment with data for natural alkaloids of the palau'amine family. This comparison provides convincing evidence in favor of the recently proposed structural revision of these marine alkaloids, fully supporting the trans configuration of the central azabicyclo[3.3.0]octane ring system of palau'amine and congeners.
Project description:Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvone-derived fragments, facilitated by Pd-catalyzed C-C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visible-light induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.
Project description:The cyclopentane core of palau'amine has been constructed in optically pure form through the use of an asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction.
Project description:This study highlights psychometric properties and evidence of construct validity on parcel-level for questionnaires on the original and revised reinforcement sensitivity theory. Our data (N = 1,076) suggest good to very good psychometric properties and moderate to excellent internal consistencies. Confirmatory factor analysis (CFA) models suggest a very good model fit for the first-order, four factor models of the Carver-White BIS/BAS scales, Reinforcement Sensitivity Theory - Personality Questionnaire (RST-PQ), the two-factor model of revised Reinforcement Sensitivity Theory-Questionnaire (rRST-Q) and for the bifactor model of the Conflict Monitoring Questionnaire (CMQ-44). The CMQ-44 extends the psychometric measurement of previous trait-(r)BIS and trait-BAS scales. Factor scores of CMQ-44 cognitive demand correlate positively with factor scores of Carver-White BIS and all Carver-White BAS subfactors except RST-PQ-Impulsivity suggesting that CMQ-44 cognitive demand addresses Carver-White trait-BIS specifically and more generally the trait-BAS core. CMQ-44 anticipation of negative consequences and response adaptation correlate negatively with trait-BAS, whereas the second-order factor performance monitoring extends the rRST trait-space and correlates positively with trait-BAS.
Project description:Palau'amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here we report the total synthesis of palau'amine characterized by the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N-N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation) and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The synthetic palau'amine is confirmed to exhibit excellent immunosuppressive activity. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity.
Project description:The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.
Project description:Two sediment cores collected from Lake Ontario and Lake Erie were sectioned, dated, and analyzed for five polycyclic musk fragrances and two nitro musk fragrances. The polycyclic musk fragrances were HHCB (Galaxolide), AHTN (Tonalide), ATII (Traseolide), ADBI (Celestolide), and AHMI (Phantolide). The nitro musk fragrances were musk ketone and musk xylene. Chemical analysis was performed by gas chromatography/mass spectrometry (GC/MS), and results from Lake Erie were confirmed using gas chromatography/triple-quadrupole mass spectrometry (GC/MS/MS). The chemical signals observed at the two sampling locations were different from each other primarily because of large differences in the sedimentation rates at the two sampling locations. HHCB was detected in the Lake Erie core whereas six compounds were detected in the Lake Ontario core. Using measured fragrance and 210Pb activity, the burden of synthetic musk fragrances estimated from these sediment cores is 1900 kg in Lake Erie and 18 000 kg in Lake Ontario. The input of these compounds to the lakes is increasing. The HHCB accumulation rates in Lake Erie for 1979-2003 and 1990-2003 correspond to doubling times of 16 +/- 4 and 8 +/- 2 years, respectively. The results reflect current U.S. production trends for the sum of all fragrance compounds.
Project description:PurposeAnti-Müllerian hormone (AMH) is used as a marker for ovarian reserve. Since 2011, the standard test for AMH has been the Beckman Coulter Generation (Gen) II assay. However, in July 2013, the protocol was revised due to falsely low readings. The aim of this study was to compare AMH levels measured with the original and revised Gen II assay and to establish a fertile female reference range for the revised protocol.MethodsSerum AMH levels were measured for 492 natural conception first trimester pregnant women using the original and revised Gen II assay.ResultsThe original protocol significantly underestimated AMH levels compared with the revised protocol (p < 0.001), the median being 8.4 and 14.2 pmol/L, respectively. In all samples with detectable AMH levels, the revised protocol yielded a higher concentration compared with the original protocol, the magnitude shift ranging from 3.4 to 283.3 % (median 68.0 %). AMH levels measured with the revised protocol were collated to generate an age-specific reference range, with median levels peaking at 27 years then declining with advancing age. The median AMH concentration for ages 20-24 was 17.3 pmol/L, ages 25-29 was 20.5 pmol/L, ages 30-34 was 17.8 pmol/L, ages 35-39 was 10.8 pmol/L, and ages 40-44 was 6.1 pmol/L.ConclusionsOur study demonstrated that the original Gen II assay significantly underestimated AMH levels, suggesting caution is required when interpreting literature and testing results achieved with this assay. We also established the revised Gen II assay reference range for AMH in women with unassisted proven fertility.
Project description:A selection of cyclic and acyclic acetylenic scaffolds bearing two tetrathiafulvalene (TTF) units was prepared by different metal-catalyzed coupling reactions. The bridge separating the two TTF units was systematically changed from linearly conjugated ethyne, butadiyne and tetraethynylethene (trans-substituted) units to a cross-conjugated tetraethynylethene unit, placed in either acyclic or cyclic arrangements. The cyclic structures correspond to so-called radiaannulenes having both endo- and exocyclic double bonds. Interactions between two redox-active TTF units in these molecules were investigated by cyclic voltammetry, UV-vis-NIR and EPR absorption spectroscopical methods of the electrochemically generated oxidized species. The electron-accepting properties of the acetylenic cores were also investigated electrochemically.