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.
The antioxidative activity of liposomes co-encapsulating stereoisomer 3S,3’S-astaxanthin (Asx-S) and α-tocotrienol (α-T3) was higher than the calculated additive activity, which results from intermolecular interactions between both antioxidants. The optimal Asx-S/α-T3 ratio for antioxidation was 1:2. Consequently, the Asx stereochemistry affects the intermolecular interaction of Asx/T3, and it was suggested that the intermolecular interaction caused a change in the electronic state of the Asx-S polyene moiety by the presence of double bond in the α-T3 triene moiety.
Abnormal uterine bleeding (AUB) induced by incomplete abortion, which is a common gynecological disease. Taohong Siwu decoction (TSD) has been developed to treat AUB for hundreds of years. In this study, it demonstrated that TSD significantly shortened the duration and reduced the quantity of uterine bleeding. These results suggested that TSD promoted endometrial repair and had a protective effect on uteri. The mechanism may be concerned with up-regulation of the levels of E2 and ERα expression.
Actinobacteria are the rich source of natural products while the large parts of biosynthetic gene clusters (BGCs) are silent under the standard culture conditions. The authors previously demonstrated that co-culture with mycolic acid-containing bacterium (MACB) effectively activates the silent BGCs in actinobacteria. In this study, the authors investigated the actinobacterium which produces a polyene macrolactam, mirilactam A. The authors tested co-culture of the mirilactam A producer strain with MACB, and successfully obtained three novel polycyclic macrolactams, mirilactams C-E, by activating silent biosynthetic genes responsible for the epoxidation and cyclization of the polyene mirilactam A.
The genus Dendrobium (Orchidaceae) is comprised of more than 1,000 species and divided into two major groups, Asian and Australasian clades. There are many ethnobotanical important species in this genus and various phenanthrenes and bibenzyl derivatives have been isolated from Dendrobium in previous studies. Secondary metabolites produced by species of the Australasian clade have not been studied well, even though several species of this group have also been used as traditional herbal remedies. The authors provide an overview of secondary metabolites of Dendrobium by combined non-target metabolomics and multivariate analysis, and identified characteristic compounds from several closely related Australasian species.
article describes the estimation of the diffusion coefficients of sugars and a
related compound. A simple and handy
experimental system with agar-gel was built and used to observe diffusion of small
molecules. The correlation formulas derived from computer simulations of the
experimental diffusion system were then applied to estimate diffusion
coefficients. The values obtained for these coefficients agree reasonably well
with those published in the literature. This finding supports the efficacy of the
approach for estimating diffusion coefficients, leading to the elucidation of
the diffusion coefficients of galactose, trehalose and glycerol.
The antiparallel triplex DNA is formed by the interaction between purine-rich triplex forming oligonucleotides (TFOs) and the homo-purine region within a duplex DNA. The formation of such a structure with the genome DNA promises to control the gene expression in a living cell. In this paper, in an attempt to enhance the stability of the triplex DNAs, the authors have designed and synthesized the N2-arylated deoxyguanosine derivatives. The TFOs containing N2-phenyl-2′-deoxyguanosine (PhdG) showed a stable and selective triplex DNA formation with the GC base pair as compared to the natural dG/GC triplet.
Dolastatin 16 is a cyclic depsipeptide isolated from cyanobacterium Lyngbya majuscula, however, its bioactivity has been a historical question. In this study, FKBP1A was predicted as a potential target of dolastatin 16 via PharmMapper as well as verified using chemical-protein interactome (CPI) and molecular docking. The lowest binding energy of dolastatin 16-FKBP1A complex was -7.4 kcal/mol. The ligand dolastatin 16 formed three hydrogen bonds and seven hydrophobic interactions within the active site residues. And the pharmacophore model was shown feasibly matching with the molecular feature of dolastatin 16.
Photographs of tropical and subtropical plants of Madagascar, Thailand, Vietnam, Indonesia and Okinawa, Japan by courtesy of the authors. And some chemical structures of new compounds isolated from these plants are shown. Upper left: Macaranga tanarius and a prenylflavanone, Upper middle: Senna siamea, Upper right: Croton tonkinensis and an ent-Kaurane diterpene, Middle left: Rhinacanthus nasutus, Central middle: Baobab; Adansonia grandidieri, Middle right: Impatiens balsamina, Lower left: Artemisia roxburghiana and X-ray crystallography of a guaianolide, Lower middle: Justicia gendarusa, Lower right: Croton cascarilloides and a plausible biosynthetic pathway of new skeletons.