In spite of only a few naturally occurring products having one or more fluorine atoms, organofluorine compounds have been widely utilized in pharmaceutical, agrochemical, and functional material science fields due to the characteristic properties of the fluorine atom. Therefore, the development of new methods for the introduction of fluorine-containing functional groups has been a long-standing research topic. This article discusses our contributions to this area. The first topic is on the trifluoromethylations of C–C multiple bonds using Togni reagent based on our working hypothesis that hypervalent iodine could be activated by coordination of the carbonyl moiety to the Lewis acid catalyst. The second topic relates to asymmetric fluorofunctionalization of alkenes. A newly designed phase-transfer catalyst consisting of a carboxylate anion functioning as a phase-transfer agent and a primary hydroxyl group as a site that captures the anionic substrate was revealed to be an effective catalyst for asymmetric fluorolactonization. Inspired by the mechanistic studies of fluorolactonization, we produced a linked binaphthyl dicarboxylate catalyst, which catalyzes the 6-endo-fluorocyclization and the deprotonative fluorination of allylic amides in a highly enantioselective manner. The third topic is on C–H fluorofunctionalizations using either catalysis or photoactivation. Benzylic trifluoromethylation, which is still a rare reaction, using Togni reagent and aromatic C–H trifluoromethylation using Umemoto reagent under simple photoirradiation conditions were achieved. In addition, the Csp3–H fluorination of alkyl phthalimide derivatives is demonstrated.
Introduction of a fluorofunctional group into
organic compounds has been an important topic in the pharmaceutical science
field. Although various types of fluorofunctionalizations have been actively
investigated so far, applicable substrates are still limited and the
development of a new methodology for the preparation of new materials having
fluorofunctional groups is in high demand. In this personal account, 1)
trifluoromethylations of C–C multiple bonds, 2) asymmetric
fluorofunctionalizations of alkenes, and 3) C–H fluorofunctionalizations, which
have been reported by the author and co-workers, are described.
Inhibition of myostatin is a promising strategy for treatment of muscle atrophic disorders. A 16-mer myostatin inhibitory linear peptide, MIPE-1686, administered intramuscularly, significantly increases muscle mass and hindlimb grip strength in Duchenne muscular dystrophic model mice. In this paper, we describe our examination of the enzymatic stabilities of this peptide with recombinant human proteases, aminopeptidase N, chymotrypsin C, and trypsin 3. MIPE-1686 was found to be stable in the presence of these enzymes, in contrast to a peptide (1), from which MIPE-1686 was developed. Modification of the peptides at a position distant from the protease cleavage site altered their enzymatic stability. These results suggest the possibility that the stability to proteases of 16-mer myostatin inhibitory peptides is associated with an increase in their known β-sheet formation properties. This study suggests that MIPE-1686 has a potential to serve as a long-lasting agent in vivo.
Myostatin is a negative regulator of skeletal muscle
growth. Recently, the authors developed 16-mer peptidic myostatin inhibitor
MIPE-1686, which enhances muscle mass and grip strength in mice. The present
study demonstrates that a linear peptide MIPE-1686 with N-terminal unprotected
is amazingly stable against recombinant human proteases (aminopeptidase N,
etc.). This implies that MIPE-1686 has a potential to act long-lasting in
vivo. The results also suggest that the secondary structure of a relatively
small linear peptide may influence the recognition by degradation enzymes. This
would give a valuable information for designing a stable linear peptide drug in
Mohs paste is useful for controlling exudates from wounds and infections and is used to treat patients with inoperable skin tumors. Unfortunately, Mohs paste is difficult to preserve because its viscosity and stickiness increase dramatically immediately after preparation, resulting in decreased usability. In this study, the combined use of cryopreservation and kneading was shown to improve long-term storage of Mohs paste. At 25°C, Mohs pastes solidified rapidly, and viscosity reached approximately 700 Pa·s 5 h after preparation. In contrast, cryopreservation at −20°C attenuated hardening of Mohs pastes, and kneading also decreased viscosity. The viscosity of Mohs pastes cotreated with cryopreservation and kneading after 7 months of storage was <70 Pa·s. In addition, tissue invasion with these stored pastes was similar to freshly prepared Mohs paste. Results suggest that the combination of cryopreservation and kneading permits Mohs paste to be stored over extended periods, which may increase the utility of the paste for clinical use.
An asymmetric nitrogen-containing dimer, leiocarpanine A, was isolated from the aerial part of Mercurialis leiocarpa as a new compound. The new generation process of leiocarpanine A was estimated and a concise synthesis of leiocarpanine A could be detailed based on mimicking the generation process through the radical intermediates. In general, a lot of reaction step and organic reagents are required for the synthesis of asymmetric nitrogen-containing dimers. However, our new synthesis method enables a concise synthesis of asymmetric nitrogen-containing dimers through radical intermediates by only liquid-separation. This synthetic method provides a rapid and concise pathway to construct a library of nitrogen-containing dimers that might be useful for drug discovery. In addition, it is useful to elucidate the generation process of leiocarpanine A.
One of the oldest dye plants, Mercurialis leiocarpa
(Euphorbiaceae), had been used as a blue dye until indigo dye
appeared in Japan. The constituents are expected the application as medicines.
In this paper, the authors isolated a new nitrogen-containing asymmetric
dimer, leiocarpanine A, from the aerial parts of this plant and described the chemical
elucidation, the estimation of the generation process, and the concise
mimicking the generation process through radical intermediates. This synthetic method provides
a rapid and concise pathway to construct a library of nitrogen-containing
dimers that might be useful for drug discovery.
Inhibitors of human β-N-acetyl-D-hexosaminidase (hHEX) A and human O-GlcNAcase (hOGA) reportedly play roles in multiple diseases, suggesting their potential for pharmacological chaperone (PC) therapy of Sandhoff disease (SD) and Tay–Sachs disease (TSD), as lysosomal storage diseases, and Alzheimer’s disease and progressive supranuclear palsy, respectively. In particular, hHEXA inhibitors as PCs have been shown to successfully enhance hHEXA levels, leading to the chronic form of SD and TSD. In the diagnosis of enzyme deficiencies in SD and TSD, artificial hHEXA substrates based on 4-methylumbelliferone as a fluorophore are available and generally used; however, they do not have sufficient performance to screen for potential inhibitors for a PC therapy from compound libraries. Further, there are currently few fluorogenic substrates for hHEXA suitable for such requirements and there are no substrates ideal for cell-based inhibitor screening. Here, we clarified the difference in enzyme active site structure between hHEXA and hOGA from their tertiary structures. To develop lysosome-localized hHEXA-specific fluorogenic substrates based on the difference in their active site structures, our developed quinone methide cleavage substrate design platform was applied for the molecular design of substrates. Thereafter, we synthesized via the shortest route and evaluated novel three-color fluorogenic substrates for hHEXA that exhibited excellent specificity and sensitivity in three human cell lines. The designed substrates represent the first-in-a class of new substrates that can be utilized to screen hHEXA inhibitors in adherent human cultured cells.
Inhibitors of human β-N-acetyl-D-hexosaminidase A,
hHEXA, have the potential to a pharmacological chaperone for Sandhoff disease
and Tay-Sachs disease as lysosomal storage diseases. The hHEXA inhibitors have
been shown to successfully enhance hHEXA levels, leading to the chronic form of
these diseases. To develop hHEXA inhibitors, authors analyzed the hHEXA active site
structure and designed the specific hHEXA fluorogenic substrates based on the
authors’ substrate design platform. The designed substrates were synthesized
and these were exhibited excellent specificity and sensitivity for hHEXA in
three human cell lines. These are all new substrates that can be utilized to
screen hHEXA inhibitors in human cells.
Hydrophilic polyacrylamide gel-based triazine-type condensing reagents, PAG-Trz-Cl, have been developed. PAG-Trz-Cls were synthesized using a chlorotriazine with an acrylamide moiety, acrylamide, and N,N′-methylenebisacrylamide via both precipitation and solution polymerization. Because PAG-Trz-Cls adequately swell in aqueous media, the amidation between polar carboxylic acids and amines afforded the corresponding amides in good yields.
There is a great need for reagents
that are environmentally benign, easy to
handle, inexpensive, and safe in organic synthesis. In this context, the authors have developed hydrophilic
polyacrylamide-gel based triazine-type condensing reagents, PAG-Trz-Cls, which
were synthesized from inexpensive materials via radical polymerization. PAG-Trz-Cls
are non-hygroscopic solid, high-loading, well-swollen in water and alcohol.
Owing to these features, condensation between highly polar carboxylic acids and
amines in an aqueous solvent successfully proceeded, and purification of the
resulting amides can be readily carried out by filtration.
There are various diagnostic and therapeutic agents for prostate cancer using bombesin (BBN) derivatives, but astatine-211 (211At)-labeled BBN derivatives have yet to be studied. This study presented a preliminary evaluation of 211At-labeled BBN derivative. Several nonradioactive iodine-introduced BBN derivatives (IB-BBNs) with different linkers were synthesized and their binding affinities measured. Because IB-3 exhibited a comparable affinity to native BBN, [211At]AB-3 was synthesized and the radiochemical yields of [211At]AB-3 was 28.2 ± 2.4%, with a radiochemical purity of >90%. The stability studies and cell internalization/externalization experiments were performed. [211At]AB-3 was taken up by cells and internalized; however, radioactivity effluxed from cells over time. In addition, the biodistribution of [211At]AB-3, with and without excess amounts of BBN, were evaluated in PC-3 tumor-bearing mice. Despite poor stability in murine plasma, [211At]AB-3 accumulated in tumor tissue (4.05 ± 0.73%ID/g) in PC-3 tumor-bearing mice, which was inhibited by excess native BBN (2.56 ± 0.24%ID/g). Accumulated radioactivity in various organs is probably due to free 211At. Peptide degradation in murine plasma and radioactivity efflux from cells are areas of improvement. The development of 211At-labeled BBN derivatives requires modifying the BBN sequence and preventing deastatination.
The water quality in a river (water environment) is very important for human health and aquatic organisms. In 2015, the highly regarded Water Resources Management Strategy of Thailand was announced by The Ministry of Industry in Thailand. In this study, the water quality of the Ping river in Northern Thailand, including Chiang Mai and Lamphun provinces, was focused on and measured for three different seasons (summer, rainy, and winter seasons). Anions (F−, Cl−, NO2−, NO3−, and SO42−) and cations (Na+, Mg2+, Si4+, S6+, K+, and Ca2+) were qualified by an ion chromatograph and an inductively coupled plasma optical emission spectrometry, respectively. The concentration of anions and cations (except for Mg2+ and Ca2+) in the Ping river at upstream (countryside) locations were lower than that at downstream (closer main city) locations, which indicated that the fertilizers, industrial or household wastewaters had been flowing into the Ping river at downstream locations. Additionally, the concentration of anions and cations in the rainy season was higher than other seasons. The present results provide the water quality of the Ping river which was not yet reported officially by the Thailand government.
α,β-Unsaturated amides were incorporated as viable dipolarophiles in a catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines. The use of a 7-azaindoline auxiliary was essential to acquire sufficient reactivity with excellent diastereoselectivity, likely due to the chelating activation of the amide by the In(III)/bishydroxamic acid complex. Although the enantioselectivity remains unsatisfactory, this work is an important step toward the development of an asymmetric catalysis utilizing stable and low-reactive substrates.
The regioselective synthesis of both 2- and 3-alkoxyindoles from a common intermediate, 2-alkoxy-3-bromoindolines (ROBIN), is described. The 2-alkoxyindoles are obtained by a base-promoted regioselective elimination of HBr from ROBIN, whereas the synthesis of 3-alkoxyindoles is achieved by a silver-mediated alkoxylation followed by an acid-promoted elimination of alkoxide. This key elimination features the complete regioselectivity and no need for catalysts, that makes it have potential synthetic applications. Furthermore, this protocol is user friendly because ROBIN is able to be prepared from commercially available indoles and is a bench-stable easy-to-handle crystalline substrate, thus allowing the concise synthesis of a variety of both 2- and 3-alkoxyindoles.