To date, little is known about the evolution of fern genomes, with only two small genomes published from the heterosporous Salviniales. Here we assembled the genome of Alsophila spinulosa, known as the flying spider-monkey tree fern, onto 69 pseudochromosomes. The remarkable preservation of synteny, despite resulting from an ancient whole-genome duplication over 100 million years ago, is unprecedented in plants and probably speaks to the uniqueness of tree ferns. Our detailed investigations into stem anatomy and lignin biosynthesis shed new light on the evolution of stem formation in tree ferns. We identified a phenolic compound, alsophilin, that is abundant in xylem, and we provided the molecular basis for its biosynthesis. Finally, analysis of demographic history revealed two genetic bottlenecks, resulting in rapid demographic declines of A. spinulosa. The A. spinulosa genome fills a crucial gap in the plant genomic landscape and helps elucidate many unique aspects of tree fern biology.
Peptide modification methods that do not rely on the cysteine residue are underdeveloped, and their development could greatly expand the current toolbox for peptide chemistry. During the course of preliminary investigations into the classical ortho-phthalaldehyde (OPA)-amine-thiol condensation reaction, we found that in the absence of thiol, OPA readily condenses with two primary alkyl amines to form a class of underexplored isoindolin-1-imine compounds under mild aqueous conditions. From the intramolecular version of this OPA-2amines reaction, an efficient and selective methodology using mild reaction conditions has been developed for stapling unprotected peptides via crosslinking of two amino groups in both an end-to-side and side-to-side fashion. The stapling method is superfast and broadly applicable for various peptide substrates with the reacting amino groups separated by a wide range of different amino acid units. The macrocyclization reactions of selected substrates are completed within 10 seconds at 5 mM concentration and within 2 minutes at 50 μM concentration. Importantly, the resulting cyclized peptides with an isoindolinimine linkage can be extended in a one-pot sequential addition manner with several different electron-deficient π electrophiles, thereby generating more complex structures.
The distinct pharmacodynamic and pharmacokinetic properties of enantiopure sulfoxide drugs have stimulated us to systematically investigate their chiral separation, stereochemical assignment, and chiral recognition mechanism. Herein, four clinically widely-used sulfoxide drugs were chosen and optically resolved on various chiral stationary phases (CSPs). Theoretical simulations including electronic circular dichroism (ECD) calculation and molecular docking were adopted to assign the stereochemistry and reveal the underlying chiral recognition mechanism. Our results showed that the sequence of calculated mean binding energies between each pair of enantiomers and CSP matched exactly with experimentally observed enantiomeric elution order (EEO). It was also found that the length of hydrogen bond might contribute dominantly the interaction between two enantiomers and CSP. We hope our study could provide a fresh perspective to explore the stereochemistry and chiral recognition mechanism of chiral drugs.
A series
of conformationally constrained novel benzo[1,3]oxazinyloxazolidinones
were designed, synthesized, and evaluated on their activities against Mycobacterium tuberculosis, Gram-positive bacteria, and
Gram-negative bacteria. The studies identified a new compound 20aa that displayed good to excellent antibacterial and antitubercular
profiles against drug-resistant TB strains (MIC = 0.48–0.82
μg/mL), MRSA (MIC = 0.25–0.5 μg/mL), MRSE (MIC
= 1 μg/mL), VISA (MIC = 0.25 μg/mL), and VRE (MIC = 0.25
μg/mL) and some linezolid-resistant strains (MIC 1–2
μg/mL). Compound 20aa was demonstrated as a promising
candidate through ADME/T evaluation including microsomal stability,
cytotoxicity, and inhibition of hERG and monoamine oxidase. Notably, 20aa showed excellent mouse PK profile with high plasma exposure
(AUC0–∞ = 78 669 h·ng/mL), high
peak plasma concentration (C
max = 10 253
ng/mL), appropriate half-life of 3.76 h, and superior oral bioavailability
(128%). The present study not only successfully provides a novel benzo[1,3]oxazinyloxazolidinone
scaffold with superior druggability but also lays a good foundation
for new antibacterial drug development.
Seco and nor-seco isodhilarane-type
meroterpenoids (SIMs and NSIMs) are mainly found in Penicillium fungi and have been characterized by highly congested polycyclic
skeletons and a broad range of bioactivities. However, the literature
reports inconsistent configuration assignments for some SIMs and NSIMs,
due to their complex polycyclic systems and multichiral centers. Herein,
we described eight SIMs and NSIMs isolated from the EtOAc extract
of Penicillium purpurogenum, which led to the configuration
revisions of purpurogenolide C (1a), berkeleyacetal B
(2a), chrysogenolide F (3a), and berkeleyacetal
C (4a) as compounds 1–4, respectively. Furthermore, extensive re-evaluation of the experimental
and computational 13C NMR chemical shifts of the reported
39 SIMs and NSIMs provided an empirical approach for determining the
C-9 relative configuration, according to the 13C NMR chemical
shifts of C-9, which contributed to the configuration revisions of
another three SIMs (5a and 6a) and NSIMs
(7a), denoted as compounds 5–7, respectively. Biological assays indicated that compound 3 exhibited cytotoxic activity against HepG2 and A549 cell
lines with IC50 values of 5.58 and 6.80 μM, respectively.
Compounds 2–4, 8, 9, and 32 showed moderate hepatoprotective activity
at 10 μM in the APAP-induced HepG2 cell injury model.
Chirality is one of the key factors affecting the medicinal efficacy of compounds. In addition to central chirality, sterically hindered chiral axes commonly appear in drugs and the resulting chirality is known as atropisomerism. With developments in medicinal chemistry, atropisomerism has attracted increasing attention. This review discusses the classification, biological activity, pharmacokinetics, toxicity and side effects of atropisomers, and can serve as a reference in the research and development of potential chiral drugs.
Establishing the absolute configuration of flexible molecules is difficult, and specific optical rotation (SOR) might be an optional strategy. However, complex conformation distributions inevitably generate ambiguous results. Herein, the relationship between SORs and the absolute configuration of flexible molecules containing a 2‐methylbutyl residue was studied using quantum chemical calculations. The existence of a nitrogen atom might increase the uncertainty of the predicted SOR. Compared with the optical rotation calculation step, the geometry optimization step is more influential. Computational parameters including hybrid functionals, basis sets, and solvation models could exert a great effect on the Boltzmann distribution, leading to substantial variation in the SORs. To achieve unambiguous SOR prediction results for flexible molecules, the calculation needs to be performed using at least two combinations of different levels.
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