This paper describes a short total
synthesis of (+)-spinoxazine B, which inhibits NO production in BV-2 microgrial
cells. The synthesis features a double cyclization to rapidly construct the
bicyclic skeleton of spinoxazine B. Spinoxazine B is the first example of a
natural alkaloid containing an oxazinone-pyrrolidone nucleus. Because new ring
system is considered to be a new resource for drug discovery, spinoxazine B is
expected to serve as a novel drug lead compound as well as a drug discovery
A TLC-based simple and convenient
method using UV-sensitive constituents as markers to identify the crude drug Polygala
Root (the root of Polygala tenuifolia
Willdenow; Japanese name “Onji”) was investigated. Twenty-three aromatic
compounds including two new compounds, polygalaonjisides A and B, were
characterized. Based on the phytochemical results obtained, a TLC method
focusing on three marker spots with Rf
values of approximately 0.4-0.5 due to tenuifolisides A and B
and 3,6′-di-O-sinapoylsucrose was proposed as a
simple and convenient test to identify Polygala Root and its single-extract
products on the market. The data presented in this paper could be useful in
stipulating a confirmation test to identify Polygala Root.
Continuous flow synthesis has drawn increasing attention
in current organic synthesis. In this paper, the authors demonstrate a new
entry for the beneficial application of a microflow reactor to the synthesis of
aromatic fluorinated compounds via domino benzyne generation/nucleophilic
fluorination. In particular, the high mixing ability of the flow reactor significantly
reduced the reaction times to ~10 s and improved the product yields in comparison
to their previously reported method under ordinary batch conditions. In some
cases, aryl fluorides were obtained only under microflow conditions. Thus, the
flow chemistry is the method not only for continuous chemical production but
also for achieving transformations that are otherwise inaccessible by the
conventional batch method.
novel series of pentacoordinated organotin(IV) complexes derived from L-DOPA
were designed; the synthesis was performed by a one-pot strategy. The
biological evaluation revealed that organotin complexes were substantially more cytotoxic than cisplatin and significantly more
effective than Topotecan in inhibiting the growth of leukemia, breast and lung
cancer cell lines. The
cytotoxicity depended on the nature of the substituent bonded to the aromatic
ring. The brine shrimp lethality assay was also used to determine the toxicity.
Molecular docking revealed that organotin (IV) complexes bind to the active
site of topoisomerase I. Antifungal activity was tested against species of
The i-motif is a high-order DNA structure,
forming in cytosine-rich sequences of gene promoters and telomeric regions. Due
to the limited stability of this structure under the physiological conditions,
the i-motif DNA was unknown for several years. Recently, the biological
functions of this DNA and its application have been discovered by applying
i-motif interacting agents which is showing the importance of these ligands in
uncovering the distinctive features of i-motif.
Quercetin-pivaloxymethyl conjugate (Q-POM) potentiated the activity of ampicillin, cefepime, and vancomycin against S. aureus and Enterococcus (including highly resistant strains such as hVISA, VISA, and VRE), by decreasing the MICs of these antibiotics by 4-128 folds. Q-POM was found to be partially synergistic with ampicillin and cefepime against S. aureus and Enterococcus, while it was strongly synergistic with vancomycin. Q-POM at 5 mg/L inhibited the formation of biofilms of S. aureus by 24-83% and VRE by 70%. Additionally, Q-POM inhibited the hemolytic activity of S. aureus in a dose-dependent manner.
Metal carbenoid species are known to insert into a C−H bond, C=X double bonds (X = C, N, O), and Y−H bonds (Y = N, O, Si, P, S, etc), however, a carbenoid insertion into a urea C−N bond has not yet been reported. In the article, the first urea insertion reaction of carbenoid species is described. The urea insertion reaction proceeded smoothly using Rh2(NHPiv)4, a rhodium catalyst previously designed by the authors’ group, to produce highly functionalized bridged molecules with three adjacent stereocenters.
Primary drying conditions for the commercial manufacturing were designed based on the vial heat transfer coefficient of the production lyophilizer and the drying resistance (Rp) calculated from manufacture with the pilot lyophilizer under dust-free condition. The production scale-verification study confirmed that the Rp obtained using pilot lyophilizer under dust-free condition could be available for the production lyophilizer. This scale-up theory, which bridges the gap between the laboratory scale and the production scale, is useful for the development of an efficient and robust process at production scale.
For organic synthesis in the field of pharmaceutical sciences, methodologies that can easily and quickly supply compounds with high drug-likeness is highly desirable. Based on the original catalyst design concept "Radical-Conjugated Redox Catalysis (RCRC)" established during author's research, various C(sp3)-H functionalizations and protein modifications have been developed, taking advantage of high reactivity and chemoselectivity of single-electron transfer process. This review will focus on the research concept and efforts over eight years of the author and his collaborators.
Allylic fluoride is a useful synthetic intermediate for the preparation of various organofluorine compounds. The authors demonstrated a highly enantioselective fluorination of cyclic tetrasubstituted alkenes with a pendant amide group using their dianionic phase-transfer catalyst. The deprotonative fluorination mainly proceeded in preference to the intramolecular nucleophilic attack of the amide group, and the corresponding allylic fluorides with a chiral tetrasubstituted carbon center were obtained with up to 97% ee.
The amlodipine dissolution from orally disintegrating tablets (ODTs) in vivo in the human oral cavity was examined. Various amlodipine ODTs with different levels of physical masking effectiveness were manufactured. The present results are the first to show that drug dissolution from ODT is dependent on time in the oral cavity and coating amount. The mimicking of the inside of the human oral cavity is accurate with a testing time of 30 s, while the Tricorptester method was the most preferable of all in vitro short dissolution test methods investigated in this study.
This paper describes the development of the planar chiral [2.2]paracyclophane-based bisoxazoline (PCP-Box) ligands for Cu-catalyzed O-H insertion reactions of α-diazo esters. C2-symmetric PCP-Box ligands, in which the achiral oxazoline unit is located at the meta-position of the benzene spacer having a bulky substituent at the para-position, gave better levels of enantioselectivity in ethanolic O-H insertion than the spacer free PCP-Boxes with or without central chirality of the oxazoline rings. The former also showed good enantioselectivities in inter- and intramolecular aromatic O-H insertions.
A novel aerobic manganese-catalyzed oxophoshporylation reaction of carbon–carbon double bonds of styrene derivatives and vinyl ethers using diethyl H-phosphonates was developed. This direct transformation of alkenes to b-ketophosphonates readily proceeded at room temperature via the incorporation of molecular oxygen present in air (open flask). All of the experimental procedures in this reaction can be performed in air without cooling, heating, or high pressure. This methodology serves an alternative approach to produce β-ketophosphonates because of its simplicity and mildness.
4-epi-Jaspine B derivatives containing a polar functional group in the lipid tail were designed and synthesized for the development of sphingosine kinase (SphK) inhibitors, which would be applicable to the treatment of autoimmune and inflammatory disorders. A biological evaluation revealed that the replacement of one methylene at the lipid tail with ether oxygen affected the inhibitory activity of 4-epi-jaspine B, leading to the identification of a selective SphK2 inhibitor.
Antibody therapies that bind to PD1 protein and inhibit its binding with PDL1 protein have shown unprecedented clinical success in activating innate immune system to treat cancer. Here, the authors investigated activity of several macrocyclic compounds in inhibiting PD1-PDL1 interaction, leading to identification of Rifabutin, an approved macrocyclic antibiotic, as top active compound with remarkable IC50 value of ~25 µM. Computational docking followed by molecular dynamics simulations revealed Rifabutin making key interactions with PD1, occupying and blocking majority of the area on PD1 protein where PDL1 is known to bind.
The authors developed a novel cryogenic milling technique in liquid nitrogen (LN2) using dry ice beads. The contamination issue related to fragments of eroded beads could be overcome due to their spontaneous removal. In this study, the transformation process from the pellets and the morphological change of dry ice beads during milling process in LN2 was monitored to assess their potential as milling media. The authors presented that dry ice could maintain its bead shape even under vigorous agitation in LN2. Further, they demonstrated that their milling performance was comparable to conventional technique using zirconia beads.
The authors developed a rapid and efficient analytical technique for cyclosporine A using HPLC. Under optimized conditions, cyclosporine A was separated with high resolution from other cyclic peptides within 3 min, because the mass transfer resistance in the stationary phase was reduced by the use of the small, nonporous particle columns. The results indicate that cyclosporine A is structurally rigid and undergoes poor water solvation even at high temperature. In the context of the rapid development of cyclic peptides with similar physicochemical characteristics to cyclosporine A, the developed method is useful for the development of cyclic peptide therapeutics.
Fuligocandin B isolated from the slime mold Fuligo candida induced apoptosis in TRAIL resistance cancer cells by increasing death receptor 5 (DR5) thorough binding to valosin-containing protein (VCP). Heterocyclic derivatives of fuligocandin B were synthesized and evaluated. Amine derivative designed based on docking simulation showed potent cytotoxicity against TRAIL resistance human gastric adenocarcinoma (AGS) cells. The figure represents picture of Fuligo candida, structure of 7’-amino fuligocandin B and image of increasing DR5 which goes to bind to TRAIL on the cell surface.
The triangle contour diagram of the Hausner ratio (HR) was represented as a function of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC). The HR is given as the ratio of tapped density to bulk density of powders, and the value is often used as an index of powder fluidity. Although the fluidity of most formulations was acceptable, an increase in the amount of MCC led to poor fluidity (high HR values), which suggested that the upper limit of MCC was required to secure better fluidity of premix powders.
New Zn(II), Mg(II), Ni(II), Cu(II), Pd(II), and Ag(I) complexes of 2-trifluoroacetonylbenzoxazole ligand have been synthesized. Their structures were determined by single-crystal X-ray diffraction analyses. Some metal complexes have more antibacterial effects in comparison with the free ligand. Noticeably, the Ag(I) complex 2h exhibited low MIC value of 0.7 μM against Pseudomonas aeruginosa, which was even superior to Norfloxacin with that of 1.5 μM. 2h is bacteriostatic, exerts the cell surface damage observed by scanning electron microscopy and is less likely to develop resistance. 2h has been found to display effective antimicrobial activity against a series of bacteria.