This review reports on the development of new synthetic methods using oxiranyl anions and their application to the synthesis of polycyclic ether marine natural products. Novel iterative and convergent methods for large, complex polycyclic ether structures have been devised. In these, the reactions of sulfonyl-stabilized oxiranyl anions were employed to construct trans-fused polyether ring systems, along with 6-endo cyclization and ring expansion reactions. Total syntheses of polycyclic ether marine toxins, viz. hemibrevetoxin B, gambierol, and gymnocin-A, were achieved based on the oxiranyl anion strategy developed.
Oxiranyl anions are very unstable and uncommon
nucleophiles while epoxies are widely used as electrophiles in organic chemistry.
A sulfonyl-stabilized oxiranyl anion reacts efficiently with a triflate to afford
an alkylated product in high yield. The high synthetic potential of the
oxiranyl anion chemistry was demonstrated by the total synthesis of gymnocin-A,
a cytotoxic polycyclic ether marine natural product produced by the red tide
organism Karenia mikimotoi.
In our quest for structurally intriguing compounds from Korean medicinal plant sources, chromatographic separation of the 80% MeOH extract from Firmiana simplex resulted in the isolation and identification of three new lignan glycosides (1–3), together with six known lignan glycosides (4–9). The structures of 1–3 were determined on the basis of spectroscopic analyses, including extensive 2D-NMR and enzyme hydrolysis. Nitric oxide (NO) production was evaluated in the lipopolysaccharide-activated microglial cell line, BV-2 to investigate the anti-neuroinflammatory effects of the isolated compounds (1–9). Compound 7 marginally inhibited NO levels with IC50 values of 59.83 µM.
Metformin is a euglycemic drug for the treatment of type 2 diabetes mellitus. To date, there are 13 dissolution methodologies described in the U.S. Pharmacopoeia (USP) to evaluate the release profile of metformin from extended-release tablets utilizing either a USP apparatus 1 (basket) or 2 (paddle). In the absence of a protocol for a USP apparatus 3 (reciprocating cylinder), the goal of this work was to develop an in vitro dissolution method for metformin extended-release tablets based on an in vivo–in vitro correlation (IVIVC). Following a systematic evaluation, a final dissolution method, M4, was defined. It applied 30 dips per minute (dpm) over a total period of 10 h into a series of solutions that included 2 h in HCl media (pH 1.2), 1 h in an acetate buffer solution (pH 4.5), 1 h in phosphate buffer solution (PBS) (pH 5.8) and 6 h in PBS (pH 6.8). This method showed a significant IVIVC with a calculated R2 > 0.98 (point-to-point correlation, Level A) and it was successfully used as a tool to assist in the development of generic extended release formulations for metformin consisting of a lipophilic matrix system.
Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time-consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease–disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs.
Polygenetic and complex diseases are great burden
and challenge of human, such as ischemic cerebrovascular disease (ICD) and
cardiovascular diseases (CVD). Drug repositioning, is one important approach to
reexamine the new indications of marketed drugs, especially drugs with
multi-targets. Based on the interplay among diseases, genes (targets) and
drugs, new method can be applied to dissect the association information. A
multi-database, in silico target identification, gene function enrichment, and
network pharmacology analysis integrated methods were proposed to investigate
the approved CVD drugs repurposing for ICD. It provides promising alternative
to inferring novel disease indications for existing safe and effective drugs.
Bio-guided fractionation of the 70% ethanol extract of Belamcanda chinensis (L.) DC. revealed four new compounds, including 6″-O-acetylembinin (5), 3″-O-acetylembinin (6), irigenin 3′-O-β-glucopyranoside (8), and 2′-acetyl-1,3-O-diferuloylsucrose (9), along with five known compounds (1–4, 7). Their chemical structures were determined using extensive NMR data, mass spectroscopy, and comparison with published literature. Among the isolates, compounds 1 and 4–7 achieved good regulation of the growth and proliferation of vascular smooth muscle cells.
A series of 8-methoxy or 8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole derivatives at the C-7 position was synthesized, and the pharmacological, physicochemical, and toxicological properties of the individual compounds were evaluated. Novel 8-methylquinolone 7, which includes a 3-amino-7-fluorooctahydrocyclopenta[c]pyrrole moiety at the C-7 position, showed potent antibacterial activity against both Gram-positive and negative pathogens. Compound 7 also demonstrated favorable pharmacokinetic and pharmacodynamic properties and an acceptably safe toxicological profile. Consequently, compound 7 was selected as a clinical candidate.
A series of 8-methoxy or
8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole
derivatives at the C-7 position was synthesized, and the pharmacological,
physicochemical, and toxicological properties of the individual compounds were
evaluated. Novel 7-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-8-methylquinolone
7 exhibited potent and better activity than
LVFX and MFLX against streptococci, staphylococci, enterococci, E. coli, A. baumannii, and anaerobes. Compound 7 also demonstrated favorable
pharmacokinetic and pharmacodynamic properties and an acceptably safe
toxicological profile. Consequently, compound 7 was selected as a clinical candidate for further evaluation as a new-generation,
broad-spectrum quinolone antibiotic. Compound 7 is expected to become an option for antibacterial therapy against multidrug-resistant A.
baumannii.
The present study proposes a method for the assessment of repeatability in supercritical fluid chromatography with electrochemical detection (SFC-ECD), based on the ISO 11843 part 7 (ISO 11843-7:2018) which can theoretically provide detection limits and standard deviation (S.D.) through the stochastic properties of baseline noise without repetitive measurements of real samples. On the baseline noise of SFC-ECD, large-amplitude and periodic noises with less than 0.05 Hz were observed, and the power spectrum of the baseline noise showed 1/f fluctuation (f = frequency). It was found that the present power spectrum analysis, according to the law of error propagation, can provide suitable noise parameters to calculate S.D. of baseline noise and a relative S.D. (RSD) of peak area by ISO 11843-7. The chromatographic determinations of α-, β-, γ- and δ-tocopherol have been taken as examples. In the present SFC-ECD, the RSDs of peak areas for α-, β-, γ- and δ-tocopherol obtained by ISO 11843-7 were within 95% confidence intervals of the RSD of them obtained by repetitive measurements (n = 6). Thus, we found that ISO 11843-7 is applicable to the assessment of repeatability in SFC-ECD for determining tocopherols without repetitive measurements.
Assessment
of repeatability in supercritical fluid chromatography with electrochemical
detection (SFC-ECD) system is necessary to construct an SFC-ECD as a
quantitative method with satisfactory precision. This article is the first report that a
method for the assessment of repeatability in SFC-ECD has been proposed by
means of the ISO 11843 part 7 which can theoretically provide detection limits
and standard deviation (SD) through the stochastic properties of baseline noise
without repetitive measurements of real samples. The present method is practically useful,
and both experimental time and chemicals can be saved to estimate the
repeatability in SFC-ECD.
An alternative synthetic route toward a key intermediate in the total synthesis of isoschizogamine is described. The Claisen–Johnson rearrangement stereoselectively constructed a quaternary carbon. Trifluoroperacetic acid mediated the Baeyer–Villiger oxidation to form a bicyclic lactone. The Mukaiyama–Matsuo protocol converted the lactone into an α,β-unsaturated lactone, that was used as the substrate for the rhodium-mediated 1,4-addition of an arylboronic acid.
Isoschizogamine is a member of the schizozygane family of indole
alkaloids. Its highly fused hexacyclic structure containing an aminal adjacent
to a quaternary stereocenter makes it a challenging synthetic target. While the authors reported the total synthesis of
(–)-isoschizogamine in 2012, this paper describes an alternative preparation of
their pivotal synthetic intermediate. The synthesis features a stereoselective
construction of a quaternary carbon by the Claisen-Johnson rearrangement and a
stereoselective rhodium-mediated 1,4-addition of arylboronic acid. The
reliability of this synthetic route enables a
sufficient supply of the intermediate for the total synthesis of isoschizogamine.
A facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in β-hydroxy esters, furnishing α,β-unsaturated esters in shorter steps than the previous method: an acetylation of β-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,β-unsaturated esters.
The absolute configuration of (+)-4-(6-methoxy-2-naphthyl)butan-2-ol ((+)-MNBO), a nabumetone metabolite, was determined using 1-fluoroindan-1-carboxylic acid (FICA). Both enantiomers of the FICA methyl esters were derivatized to diastereomeric esters of (+)-MNBO by an ester exchange reaction. The results of 1H- and 19F-NMR spectroscopy of the diastereomeric FICA esters of (+)-MNBO confirmed the absolute configuration of (+)-MNBO was (S).