C–H functionalization reactions involve the activation of otherwise unreactive C–H bonds, and represent atom economical methods for the direct transformation of simple substrates to complex molecules. While transition metal-catalyzed C(sp²)–H functionalization reactions are regularly used in synthesis, C(sp³)–H functionalization is rarely applied to the synthesis of complex natural products because of the difficulties associated with controlling selectivity. With this in mind, we focused on the development of new palladium (Pd)(0)-catalyzed C(sp³)–H functionalization reactions for the synthesis of complex molecules, resulting in several new methods capable of solving these problems. We initially developed a concise synthetic method for the facile construction of oxindoles and spirooxindoles via a Pd-catalyzed benzylic C(sp³)–H functionalization reaction. This method was subsequently extended to the synthesis of various heterocycles, including 2-arylindoles, benzocarbazole, indolocarbazole, indoloquinazolinone, and indoloquinazolinedione, as well as the total synthesis of several pyrrolophenanthridine alkaloids without the need for any protecting groups. This method was also successfully applied to the synthesis of the right-hand fragment of benzohopane from tetrahydro-2H-fluorene, which was constructed by a Pd-catalyzed benzylic C(sp³)–H functionalization. In this review, we provide a detailed discussion of our most recent investigations pertaining to Pd(0)-catalyzed benzylic C(sp³)–H functionalization.

The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit^® S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier.

Lubricants are essential additives in tablet formulations. Magnesium stearate (Mg-St) is the most commonly used lubricant in tableting. Here, we used sucrose fatty acid ester (SE) as an additive to manufacture tablets by direct compression. We evaluated the effects of hydrophile–lipophile balance (HLB) and the amount of SE on the flowability of a pharmaceutical powder using angle of repose and practical angle of internal friction measurements. In addition, we investigated the effects of SE on tablet properties. When SEs with an HLB ≥3 were added, the angle of repose was approximately the same as that of a pharmaceutical powder containing Mg-St, with no major differences in flowability. However, the practical angle of internal friction became closer to pharmaceutical powder containing Mg-St as HLB decreased. As HLB increased, the practical angle of internal friction approached the value of additive-free pharmaceutical powder. Tablets containing 2.0% Mg-St had a mean hardness of 40 N and disintegrated in approximately 6 min, whereas tablets containing 2.0% SE (low HLB) had a mean hardness of approximately ≥80 N and disintegrated within 3 min. The results indicate that SEs can be used as lubricants in tablet production by direct compression and to reduce problems associated with the use of Mg-St. In particular, we suggest that SEs with low HLB values can be used as excipients to achieve high tablet hardness and short disintegration time.

Two series of novel alkoxylated 2-oxo(imino)-3-pyridinecarbonitriles (structurally-relevant to some reported anticancer pyridines with phosphodiesterase 3A (PDE3A) inhibitory activity) were synthesized and evaluated for their in vitro differential tumor cell growth inhibitory potential against the breast MCF7, hepatocellular Hep-G2, colon CACO-2 cell lines, and a normal human foreskin fibroblast Hs27 cell line. Compounds 8, 16 and 19 displayed recognizable growth inhibitory ability and selectivity towards the breast MCF7 (LC₅₀ 19.15, 17.34 and 14.70 µM, respectively) as compared with doxorubicin (LC₅₀ 3.94 µM). Meanwhile, compounds 8, 15, 16, and 19 revealed a marginal inhibitory effect on the growth of the normal human foreskin fibroblast Hs27 cell line, beside a distinctive antioxidant potential in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. These four compounds were further assessed for their in vitro inhibition of PDE3A (a current antitumor therapeutic target), where 16 and 19 showed moderate to weak PDE3A inhibitory as compared with milrinone, the positive control. No clear straightforward liaison between the anticancer potential and PDE3A inhibitory activity could be deduced. Computations of the predicted pharmacokinetic properties, toxicity effects (ADME-T), drug-likeness and drug scores for the newly developed compounds showed non-violations of Lipinski’s RO5 and Veber’s criteria for good bioavailability, with a predicted high safety profile.

Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties (10, 10′, 13–15) were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a K_i value of 1.0 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (K_i=10.0 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors. Its diethyl ester prodrug 10′ was able to penetrate cell membrane and had good inhibitory effect on the growth of NCI-H522 cell xenograft tumor model.

Accurate estimation of ligand–receptor binding affinity is indispensable for computer-assisted drug discovery and structure-based drug design. Many computational scoring functions for estimating binding affinity have been proposed. Every scoring function reported so far, however, has strengths and weaknesses depending on the chemical properties of ligands and the feature of the binding site of the receptor. Hence, potential functions that can be used for many kinds of target proteins are required. In this work, we developed a software program based on Morse-type potential functions that enables evaluation of binding affinity and geometry optimization. Eight different kinds of proteins were used as test data, and ligand chemicals for which the binding pose to the protein and inhibitory constant are known were selected for evaluation. The calculated binding score and the experimentally measured inhibitory constant showed good compatibilities for six target proteins but poor correlation for one target. These compatibilities were compared with the results obtained by using two other software programs. The comparison suggested that the performance of the software developed in this work is good. Since the software can be handled in a computer facility with a many-core system, the software will be effective for search for an active compound from a chemical database and for assistance in chemical modification of the active compound in the pharmaceutical research field.

The 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene was the key starting compound used to synthesize new thiazole, pyrimidine, pyran, pyridine and thiazine derivatives. The cytotoxicity of the synthesized compounds was studied towards the three cancer cell lines namely MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (central nervous system (CNS) cancer) in addition to the normal cell line (WI-38) using doxorubicin as the reference drug. The study showed that compounds 5, 9a, 15b, 17c, 18 and 21b were the most potent compounds.

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study showed that the original formulation for the tablets led to a significant increase of unknown degradants in the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.

A moisturizing cream mixed with a steroid ointment is frequently prescribed to patients suffering from atopic dermatitis. However, there is a concern that the mixing operation causes destabilization. The present study was performed to investigate the stability of such preparations closely using magnetic resonance imaging (MRI). As sample preparations, five commercial moisturizing creams that are popular in Japan were mixed with an ointment base, a white petrolatum, at a volume ratio of 1 : 1. The mixed preparations were stored at 60°C to accelerate the destabilization processes. Subsequently, the phase separations induced by the storage test were monitored using MRI. Using advanced MR technologies including spin–spin relaxation time (T₂) mapping and MR spectroscopy, we successfully characterized the phase-separation behavior of the test samples. For most samples, phase separations developed by the bleeding of liquid oil components. From a sample consisting of an oil-in-water-type cream, Urepearl Cream 10%, a distinct phase-separation mode was observed, which was initiated by the aqueous component separating from the bottom part of the sample. The resultant phase separation was the most distinct among the test samples. To investigate the phase separation quantitatively and objectively, we conducted a histogram analysis on the acquired T₂ maps. The water-in-oil type creams were found to be much more stable after mixing with ointment base than those of oil-in-water type creams. This finding strongly supported the validity of the mixing operation traditionally conducted in pharmacies.

The dissipation of flonicamid in Honeysuckle and transfer pattern from Honeysuckle to its tea infusion were investigated. Flonicamid was applied on Honeysuckle crop at two dosages, 60 g of active gradient per hectare (g a.i. hm⁻²) and 180 g a.i. hm⁻² (recommended and triple the recommended) in Fenqiu, Henan Province in 2015 and 2016. Gas Chromatography-Electron Capture Detector (GC-ECD) detection methods were developed for the analysis of flonicamid residues in honeysuckles and its infusion. The recoveries in both honeysuckles and its infusion ranged from 81.5 to 101.7% with relative standard deviations (RSDs) of 3.2–9.1%. The dissipations of flonicamid in Honeysuckle were found to follow the first order kinetics with half-life ranging between 2.8 and 3.2 d. After recommended dose pesticide application, contents of flonicamid residues were lower than theoretical maximum residue limit (tMRL). Flonicamid residues can easily transfer from Honeysuckle to its tea infusion and transfer rates of flonicamid decrease with the brewing temperature reduction or the brewing times increase. These results are helpful to establish maximum residue limit and develop guidance on the appropriate and secure use of flonicamid in Honeysuckle.

A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.

Five novel nucleoside analogs with mono or bis-hydroxymethylated cyclopropane rings at the N⁹-position of the 2-chloroadenine moiety (2-chloro-carbocyclic oxetanocin A [COA-Cl] analog) were synthesized and evaluated using human umbilical vein endothelial cells. All the prepared compounds (2a–e) showed good to moderate activity with angiogenic potency. cis-2′-(Hydroxymethyl)cycloprop-1′-yl derivative (2b) at 100 µM had greater angiogenic activity than the other compounds did, with relative tube areas of 2.71±0.45 (mean±standard deviation (S.D.)), which was superior to the potency of COA-Cl (2.30±0.59).