The biologically active, naturally occurring 1,2,3,4-tetrahydroisoquinoline-quinone (THIQ) family members isolated from Actinomycetes and marine organisms have been studied thoroughly over the past five decades. Among them, marine natural products along with their reduced compounds, such as renieramycins and ecteinascidins, have attracted interest due to their fantastic structures and meager availability in nature as well as their potent antitumor profiles. As part of our search for new anticancer metabolites through the isolation and characterization of anticancer THIQ compounds from Thai marine animals, we have developed a fascinating THIQ natural product chemistry and medicinal chemistry based on knowledge of the chemistry of saframycin antibiotics as well as their isolation, characterization, transformation, partial synthesis, and total synthesis. This review mainly presents our contributions during 1999–2019 to the field of research on biologically active renieramycin along with ecteinascidin marine natural products.

C1q/tumor necrosis factor (TNF)-related protein 12 (CTRP12) plays a crucial part in cardiovascular diseases especially the coronary artery disease. Nonetheless, it is unrevealed that whether the CTRP12 participates in the progress of cardiac fibrosis. In this study, we investigated whether CTRP12 regulates pathological myocardial fibrosis. We isolated neonatal rat cardiac fibroblasts were cultured with recombination CTRP12 followed by stimulating with Isoproterenol (ISO, 100 µM) for 24 h. Then the adenovirus were used to achieve the CTRP12-overexpressed fibroblasts. In vivo, the C57/B6 mice were subjected to recombinant human CTRP12 (0.2 µg/g/d) for 2 weeks after injected with Isoproterenol (ISO, 10 mg/kg/d for 3 d then 5 mg/kg/d for 11 d, subcutaneously (s.c.), 2 weeks) and mice were also subjected to adenovirus with P38 overexpressing system to explore the mechanism. As a result, CTRP12 significantly inhibit the transformation of cardiac fibroblasts to myofibroblasts and the transcription of cardiac fibrosis-related proteins induced by ISO in vitro. The administration of CTRP12 can effectively reduce the cardiac fibrosis and enhance the cardiac function in mice hearts. The treatment with CTRP12 did not change the expression level of phosphorylated (p)-smad2, smad4, p-extracellular regulated protein kinases 1/2 and c-Jun N-terminal kinase 1/2, but it suppressed the activation of p38. Cardiac overexpression of p38 could abolish this kind of cardioprotective effects by CTRP12. In summary, the CTRP12 protect against the ISO induced cardiac fibrosis via suppressing the p38 signal pathway.

In the drug formulation process, compound dissolution rate and wettability may be improved by grinding. However, there is no method to understand the effects of the wettability of the crystal facets of the ground product. Here, acetylsalicylic acid (ASA) was used to evaluate the changes in crystal morphology and dissolution rate by jet milling using powder X-ray diffraction and in silico simulation. Several cleavage facets were observed in cube crystals, and the (0 0 2) facet was observed in plate crystals. Furthermore, the dissolution rate of the ground samples per unit area decreased with the cleavage of the (1 0 0) and (0 0 2) facets. The polar surface energy of the ground sample decreased with increasing grinding pressure. The simulation results showed that the absolute attachment energy of the (1 0 0) and (0 0 2) facets was lower than that of the other crystal facets. Moreover, atoms with low polarity were present on the crystal surface of (0 0 2). The wettability and dissolution rate of the (0 0 2) facet were worse than those of the (1 0 0) facet. It was suggested that the dissolution rate of the ground sample was affected by the wettability of the crystal facet caused by the cleavage. The cleavability and wettability may be understood by simulation.

The ¹³C-NMR spectral data for the 15-carbon flavonoid skeleton in eleven methoxyflavones isolated from Kaempferia parviflora (Zingiberaceae) were processed by principal component analysis (PCA). Based on the PCA score plots, the methoxyflavones were categorized into three groups according to their structural features. The cytotoxicities of the methoxyflavones toward 3T3-L1 murine preadipocyte cells were evaluated by 3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTT) assay and found to differ according to structure. The relationship between the ¹³C-NMR chemical shifts of the methoxyflavones and their cytotoxicities was investigated using Pearson’s correlation analysis. The ¹³C-NMR signal at C-10, a quaternary carbon, was correlated with cytotoxicity. Based on these results, a structural design which lowers the ¹³C-NMR chemical shift at C-10 would be important for the development of cytotoxic compounds. Although quantitative structure–activity and structure–property relationships are well established paradigms for predicting trends among a series of compounds, quantitative property–activity relationships have been relatively unstudied. This approach offers a new strategy for directing structure–activity relationship research.

Spray drying process is widely used to produce particulate materials in the pharmaceutical industries, such as porous materials for direct compression, solid dispersion for improvement of drug dissolution properties, micro encapsulation to stabilize active compounds, taste masking, preparation of dry powder for inhalation. However, as many factors affect the physical properties of dried particles and the spray drying processes have complex behaviors in which heat and mass transfer occur simultaneously, the detailed mechanisms of dry particle generation have yet to be sufficiently elucidated. In this study, computational fluid dynamics was used to simulate water droplet evaporation in a spray dryer, and the evaporation kinetics of “individual droplets” in the droplet aggregate (group) were analyzed. The numerical simulation revealed that each droplet had different evaporation rates owing to the following two reasons. First, the driving force of evaporation, ΔT, changed every moment as the droplets traveled through different temperature fields in the drying tower. Second, it was calculated the driving force for droplet evaporation differed from the ideal system because the evaporation of other droplets changed the fluid characteristics around the droplets. The obtained results are important findings that lead to the understanding the spray drying process to design and manufacture the pharmaceutical products.

As a result of the research activities of the Japan Agency for Medical Research and Development (AMED), this document aims to show an approach to establishing control strategy for continuous manufacturing of oral solid dosage forms. The methods of drug development, technology transfer, process control, and quality control used in the current commercial batch manufacturing would be effective also in continuous manufacturing, while there are differences in the process development using continuous manufacturing and batch manufacturing. This document introduces an example of the way of thinking for establishing a control strategy for continuous manufacturing processes.

A robust ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was proven effective for simultaneous characterization of six flavonoids including quercetin-3-O-beta-galactoside (Q3GAL), quercetin-3-O-beta-glucoside (Q3GLU), quercetin-3-(2-galloylglucoside) (Q3GG), kaempferol-3-O-beta-galactoside (K3GAL), kaempferol-3-O-beta-glucoside (K3GLU), and kaempferol-3-(2-galloylglucoside) (K3GG) in rat eyes. By investigation of corresponding validation parameters (linearity, selectivity, precision, accuracy, matrix effect, extraction recovery, and stability), the method was verified to be within current acceptable criteria. Thereafter, the validated method enabled quantification of the six compounds successful in rat eyes after oral administration of ethanol extract Diospyros kaki (EEDK) at 0, 3, 15, 35, 60, 120 min.

The gatekeeping adenylation (A) domain of the non-ribosomal peptide synthetase (NRPS) selectively incorporates specific proteinogenic/non-proteinogenic amino acid into a growing peptide chain. The EntE of the enterobactin NRPS is a discrete aryl acid A-domain with 2,3-dihydroxybenzoic acid (DHB) substrate specificity. Reprogrammed EntE N235G variant possesses an enlarged substrate recognition site, and is capable of accepting non-native aryl acids. Biochemical characterization of this unique substrate recognition site should provide a better understanding of activi-site microenvironments. Here, we synthesized a non-hydrolysable adenylate analogue with 2-aminobenzoic acid (2-ABA), 3-aminobenzoic acid (3-ABA), and 4-aminobenzoic acid (4-ABA) and used them to calculate the apparent inhibition constants (K_i^app.). Dose–response experiments using 3-ABA-sulfamoyladenosine (AMS) provided K_i^app. values of 596 nM for wild-type EntE and 2.4 nM for the N235G variants. These results suggest that 3-amino group of benzoic acid plays an important role in substrate recognition by the N235G variant. These findings would help designing aryl acid substrates with substituents at the 2- and 3-positions.

The MeOH extract from dried aerial parts of Oxypetalum caeruleum (Apocynaceae) plants yielded seventeen compounds, including four new tetracyclic triterpenoids, one pregnane glycoside, two lignane glycosides, and ten known compounds. The structures of the new compounds were established using NMR, MS spectroscopic analysis and chemical evidence.

The concise syntheses of two alkylated hydroquinone natural products, violaceoids A and C, were accomplished by a protecting-group-free method employing the commercially available 2,5-dihydroxybenzaldehyde as the starting material. The key strategy of the syntheses is the utilization of alkenylboronic acid as both the coupling and temporary protective reagents to efficiently introduce the requisite alkenyl side chain of violaceoid A. Moreover, the synthesis of violaceoid C is reported here for the first time.