The ability of certain oligomeric proanthocyanidins (OPACs) to enhance the biomechanical properties of dentin involves collagen cross-linking of the 1.3–4.5 nm wide space via protein–polyphenol interactions. A systematic interdisciplinary search for the bioactive principles of pine bark has yielded the trimeric PAC, ent-epicatechin-(4β→8)-epicatechin-(2β→O→7,4β→8)-catechin (3), representing the hitherto most potent single chemical entity capable of enhancing dentin stiffness. Building the case from two congeneric PAC dimers, a detailed structural analysis decoded the stereochemistry, spatial arrangement, and chemical properties of three dentin biomodifiers. Quantum-mechanics-driven 1H iterative full spin analysis (QM-HiFSA) of NMR spectra distinguished previously unrecognized details such as higher order J coupling and provided valuable information about 3D structure. Detection and quantification of H/D-exchange effects by QM-HiFSA identified C-8 and C-6 as (re)active sites, explain preferences in biosynthetic linkage, and suggest their involvement in dentin cross-linking activity. Mapping of these molecular properties underscored the significance of high δ precision in both 1H and 13C NMR spectroscopy. Occurring at low- to subppb levels, these newly characterized chemical shift differences in ppb are small but diagnostic measures of dynamic processes inherent to the OPAC pharmacophores and can help augment our understanding of nanometer-scale intermolecular interactions in biomodified dentin macromolecules.
The present study demonstrates the
importance of adequate precision when reporting the δ and J parameters of frequency domain 1H NMR (HNMR)
data. Using a variety of structural classes (terpenoids, phenolics,
alkaloids) from different taxa (plants, cyanobacteria), this study
develops rationales that explain the importance of enhanced precision
in NMR spectroscopic analysis and rationalizes the need for reporting
Δδ
and ΔJ values at the 0.1–1 ppb and 10
mHz level, respectively. Spectral simulations paired with iteration
are shown to be essential tools for complete spectral interpretation,
adequate precision, and unambiguous HNMR-driven dereplication and
metabolomic analysis. The broader applicability of the recommendation
relates to the physicochemical properties of hydrogen (1H) and its ubiquity in organic molecules, making HNMR spectra an
integral component of structure elucidation and verification. Regardless
of origin or molecular weight, the HNMR spectrum of a compound can
be very complex and encode a wealth of structural information that
is often obscured by limited spectral dispersion and the occurrence
of higher order effects. This altogether limits spectral interpretation,
confines decoding of the underlying spin parameters, and explains
the major challenge associated with the translation of HNMR spectra
into tabulated information. On the other hand, the reproducibility
of the spectral data set of any (new) chemical entity is essential
for its structure elucidation and subsequent dereplication. Handling
and documenting HNMR data with adequate precision is
critical for establishing unequivocal links between chemical structure,
analytical data, metabolomes, and biological activity. Using the full
potential of HNMR spectra will facilitate the general reproducibility
for future studies of bioactive chemicals, especially of compounds
obtained from the diversity of terrestrial and marine organisms.
This
Perspective of the published essential medicinal chemistry
of cannabidiol (CBD) provides evidence that the popularization of
CBD-fortified or CBD-labeled health products and CBD-associated health
claims lacks a rigorous scientific foundation. CBD’s reputation
as a cure-all puts it in the same class as other “natural”
panaceas, where valid ethnobotanicals are reduced to single, purportedly
active ingredients. Such reductionist approaches oversimplify useful,
chemically complex mixtures in an attempt to rationalize the commercial
utility of natural compounds and exploit the “natural”
label. Literature evidence associates CBD with certain semiubiquitous,
broadly screened, primarily plant-based substances of undocumented
purity that interfere with bioassays and have a low likelihood of
becoming therapeutic agents. Widespread health challenges and pandemic
crises such as SARS-CoV-2 create circumstances under which scientists
must be particularly vigilant about healing claims that lack solid
foundational data. Herein, we offer a critical review of the published
medicinal chemistry properties of CBD, as well as precise definitions
of CBD-containing substances and products, distilled to reveal the
essential factors that impact its development as a therapeutic agent.
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