Methyl β-d-ribofuranoside 5 and
methyl 2-deoxy-β-d-erythro-pentofuranoside
(methyl 2-deoxy-β-d-ribofuranoside) 6 were synthesized with single sites of
13C-enrichment at each carbon, and a complete set of
13C−1H
and 13C−13C spin-coupling constants (37
couplings in 5, 41 couplings in 6) in these
molecules were obtained by 1D
and 2D NMR spectroscopy. 2
J
CH
coupling signs were determined from the observation of relative
cross-peak
displacements in 2D TOCSY data. The
13C−1H couplings (one-, two-, and three-bond)
were interpreted in structural
and conformational terms with assistance from conformational models of
5 and 6 based on conventional
two-state
pseudorotational analysis of 3
J
HH
values (PSEUROT) and on theoretical predictions of conformational
energies and
J
CH values obtained from ab initio
molecular orbital calculations on the ten envelope and planar
conformers of
β-d-ribofuranose 4 and
2-deoxy-β-d-erythro-pentofuranose
(2-deoxy-β-d-ribofuranose) 3. A
comparison of theoretical
J
CH values in 3 and 4
allowed an assessment of the effect of C2 structure (C2 oxy
vs C2 deoxy) on coupling magnitudes
and signs. Results show that the behavior of related
J
CH values in 5 and 6 may
differ, especially when C2 is involved
as a coupled nucleus. In addition, several
1
J
CH,
2
J
CH, and
3
J
CH values in
β-d-ribo and
2-deoxy-β-d-ribo rings were
found to be sensitive to furanose ring and hydroxymethyl group
conformation; in the deoxyribo ring, the
presence
of diastereotopic protons at C2 produces paired
13C−1H coupling pathways involving
H2R and H2S that are
complementary, and differences in the resulting paired
J
CH values are, in some instances, sensitive to
ring conformation.
J
CC values in
β-d-ribo and
2-deoxy-β-d-ribo rings also reflect
differences in ring structure and geometry, although
fewer (e.g., 2
J
C3,C5,
3
J
C1,C5,
3
J
C2,C5) appear useful as
conformational probes. The correlations drawn between
ring
structure/conformation and
J
CH/J
CC magnitude and
sign in 5 and 6 will be useful in anticipated
applications of these
couplings to assess furanose ring conformation/dynamics in DNA and RNA
oligomers and in other biomolecules
containing β-d-ribo and
2-deoxy-β-d-ribo rings.
In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin.
Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy. Here, we describe the discovery and characterization of the nonpeptidyl compound STS-E412 (2-[2-(4-chlorophenoxy) ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine), which selectively activates the tissue-protective EPO receptor, comprising an EPO receptor subunit (EPOR) and the common b-chain (CD131). STS-E412 triggered EPO receptor phosphorylation in human neuronal cells. STS-E412 also increased phosphorylation of EPOR, CD131, and the EPO-associated signaling molecules JAK2 and AKT in HEK293 transfectants expressing EPOR and CD131. At low nanomolar concentrations, STS-E412 provided EPO-like cytoprotective effects in primary neuronal cells and renal proximal tubular epithelial cells. The receptor selectivity of STS-E412 was confirmed by a lack of phosphorylation of the EPOR/EPOR homodimer, lack of activity in off-target selectivity screening, and lack of functional effects in erythroleukemia cell line TF-1 and CD341 progenitor cells. Permeability through artificial membranes and Caco-2 cell monolayers in vitro and penetrance across the blood-brain barrier in vivo suggest potential for central nervous system availability of the compound. To our knowledge, STS-E412 is the first nonpeptidyl, selective activator of the tissue-protective EPOR/CD131 receptor. Further evaluation of the potential of STS-E412 in central nervous system diseases and organ protection is warranted.
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