cis-2-Methyl-6-substituted piperidin-3-ol alkaloids of the Cassia and Prosopis species are readily prepared by a combination of an aza-Achmatowicz oxidative rearrangement, dihydropyridone reduction followed by a Stereoselective allylsilane addition to a N-sulfonyliminium ion. The stereochemical outcome of the reduction reaction can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents and the equatorially approaching hydride reagent which explains the exclusive formation of the cis-alcohol by axial approach of the hydride. The unsaturation present in the (E)-methyl-pent-3-enoate side chain was removed by catalytic reduction and the remaining ester group was converted to the corresponding Weinreb’s amide. This key intermediate was utilized for the synthesis of azimic acid, deoxocassine, cassine and spicigerine. The facile preparation of (S)-N-tosylamidofuran 16 and its conversion to the chiral Achmatowicz oxidation product 18 provides a formal chiral synthesis of these alkaloids.
PET imaging is a widely applicable but a very expensive technology. On-site synthesis is one important contributor to the high cost. In this report, we demonstrated the feasibility of a synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18 kDa (TSPO) via a combination of disulfiram, an FDA approved drug for alcoholism, and 64CuCl2 (termed 64Cu-Dis). In this method, a step-wise injection protocol of 64CuCl2 and disulfiram was used to accomplish the purpose of synthesis-free. Specifically, disulfiram, an inactive 64Cu ligand, was first injected to allow it to metabolize into diethyldithiocarbamate (DDC), a strong 64Cu ligand, which can chelate 64CuCl2 from the following injection to form the actual PET tracer in situ. Our blocking studies, western blot, and tissue histological imaging suggested that the observed BAT contrast was due to 64Cu-Dis binding to TSPO, which was further confirmed as a specific biomarker for BAT imaging using [18F]-F-DPA, a TSPO-specific PET tracer. Our studies, for the first time, demonstrated that TSPO could serve as a potential imaging biomarker for BAT. We believe that our strategy could be extended to other targets while significantly reducing the cost of PET imaging.
The synthesis and structure–activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modu-lated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and α1-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood–brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency.
High-throughput screening (HTS) previously identified benzimidazole 1 (JMN3-003) as a compound with broad antiviral activity against different influenza viruses and paramyxovirus strains. In pursuit of a lead compound from this series for development, we sought to increase both the potency and the aqueous solubility of 1. Lead optimization has achieved compounds with potent antiviral activity against a panel of myxovirus family members (EC50 values in the low nanomolar range) and much improved aqueous solubilities relative to that of 1. Additionally, we have devised a robust synthetic strategy for preparing 1 and congeners in an enantio-enriched fashion, which has allowed us to demonstrate that the (S)-enantiomers are generally 7- to 110-fold more potent than the corresponding (R)-isomers.
Effective sensitization of triplet states is essential to many applications, including triplet-triplet annihilation based photon upconversion schemes. This work demonstrates successful triplet sensitization of a CdSe quantum dot (QD)-bound oligothiophene carboxylic acid (T6). Transient absorption spectroscopy provides direct evidence of Dexter-type triplet energy transfer from the QD to the acceptor without populating the singlet excited state or charge transfer intermediates. Analysis of T6 concentration dependent triplet formation kinetics shows that the intrinsic triplet energy transfer rate in 1:1 QD-T6 complexes is 0.077 ns-1 and the apparent transfer rate and efficiency can be improved by increasing the acceptor binding strength. This work demonstrates a new class of triplet acceptor molecules for QD-based upconversion systems that are more stable and tunable than the extensively studied polyacenes.
Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with 11C or 18F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [18F]24 and [18F]25 were found to have appropriate lipophilicities of log P7.4 = 2.2 but microPET imaging with [18F]25 demonstrated limited brain uptake.
High-throughput screening has identified 1-methyl-3-(trifluoromethyl)-N-[4-(pyrrolidinylsulfonyl)phenyl]-1H-pyrazole-5-carboxamide 16677 as a novel and potent (IC50 = 35–145 nM) inhibitor against multiple primary isolates of diverse measles virus (MV) genotypes currently circulating worldwide. The synthesis of 16677 and several analogs together with effects on MV replication is described. The most potent analog displays nanomolar inhibition against the MV and a selectivity ratio (CC50/IC50) of ca. 16,500.
Per- and polyfluoroalkyl substances (PFAS) make up a large group of fluorinated organic compounds extensively used in consumer products and industrial applications. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), the two perfluoroalkyl acids (PFAAs) with 8 carbons in their structure, have been phased out on a global scale because of their high environmental persistence and toxicity. As a result, shorter-chain PFAAs with less than 8 carbons in their structure are being used as their replacements and are now widely detected in the environment, raising concerns about their effects on human health. In this study, 47 PFAAs and their precursors were measured in paired samples of dust and drinking water collected from residential homes in Indiana, United States, and in blood and urine samples collected from the residents of these homes. Ultrashort- (with 2 or 3 carbons [C2–C3]) and short-chain (with 4–7 carbons [C4–C7]) PFAAs were the most abundant in all four matrices and constituted on average 69–100% of the total PFAA concentrations. Specifically, trifluoroacetic acid (TFA, C2) and perfluoropropanoic acid (PFPrA, C3) were the predominant PFAAs in most of the samples. Significant positive correlations (n = 81; r = 0.23–0.42; p < 0.05) were found between TFA, perfluorobutanoic acid (PFBA, C4), and perfluoroheptanoic acid (PFHpA, C7) concentrations in dust or water and those in serum, suggesting dust ingestion and/or drinking water consumption as important exposure pathways for these compounds. This study demonstrates that ultrashort- and short-chain PFAAs are now abundant in the indoor environment and in humans and warrants further research on potential adverse health effects of these exposures.
Dynamic covalent chemistry (DCvC) is a powerful means by which to rapidly prepare complex structures from simple molecular building blocks. Effective DCvC behavior is contingent upon the reversibility of covalent bond formation. Stabilized radical species, therefore, have been effectively used for these applications. In earlier work we demonstrated that properly substituted 1-arylurazolyl radicals showed promise as oxygen-insensitive heterocyclic N-centered radicals with a propensity for reversible bond formation. In this work we have synthesized several tethered bis(urazolyl) diradicals, varying by the type and length of connectivity between the urazole rings, and tested them for DCvC behavior. We have found that when the two aryl rings to which the urazolyl radical sites are attached are tethered by a chain of five or more carbons, equilibrium mixtures of monomeric and dimeric species are formed by N-N bond formation between two radical sites. DCvC behavior is observed that is sensitive to changes in temperature, concentration, and (to a lesser extent) solvent. In general, the dimer species is favored at lower temperatures and higher concentrations.