Lactose is an excipient used extensively for bulking, diluting, and molding active pharmaceutical ingredients in tablet manufacturing. Particularly, granulated lactose (GL) intended for direct powder compression has distinct properties due to differences in manufacturing methods. It contributes to handling blended powders for tableting and tablet quality. In this study, we aimed to compare the functions of different forms of GL added as excipients during direct powder compression on the tablet properties and the effect of magnesium stearate (Mg-S) used as a lubricant on each type of GL. Different GL types obtained using different manufacturing methods (agitated granulation, GL-AG; spray-dried granulation, GL-SD; fluidized bed granulation, GL-FB) were blended with maize starch, low-substituted hydroxypropyl cellulose, and paracetamol in a V-type blender for 10 min. Mg-S was added at varying amounts (0.1, 1.0, and 2.0%) and blending times (5, 10, and 30 min) for the nine types of blended powders for tableting formulation. The powders were tableted, and the tablets were evaluated for weight and drug loading variations, tensile strength, friability, and disintegration time. When tablets with the same blending conditions were compared, the tensile strength and disintegration time were in the order of GL-FB > GL-SD > GL-AG. For each GL, we analyzed the effects of changes in the added amount of Mg-S and blending time using contour plots, evaluated the effects of blending conditions on tablet properties, and determined the target tablet properties. We investigated the optimization of the lubricant blending conditions to obtain suitable tablets.

The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.

As an extension of our research on providing a chemical library of side-chain fluorinated vitamin D₃ analogues, we newly designed and synthesized 26,27-difluoro-25-hydroxyvitamin D₃ (1) and 26,26,27,27-tetrafluoro-25-hydroxyvitamin D₃ (2) using a convergent method applying the Wittig–Horner coupling reaction between CD-ring ketones (13, 14) and A-ring phosphine oxide (5). The basic biological activities of analogues, 1, 2, and 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D₃ [HF-25(OH)D₃] were examined. Although the tetrafluorinated new compound 2 exhibited higher binding affinity for vitamin D receptor (VDR) and resistance to CYP24A1-dependent metabolism compared with the difluorinated 1 and its non-fluorinated counterpart 25-hydroxyvitamin D₃ [25(OH)D₃], HF-25(OH)D₃ showed the highest activity among these compounds. Osteocalcin promoter transactivation activity of these fluorinated analogues was tested, and it decreased in the order of HF-25(OH)D₃, 2, 1, and 25(OH)D₃ in which HF-25(OH)D₃ showed 19-times greater activity than the natural 25(OH)D₃.

Jadomycins, which are benzo[b]phenanthridine-type alkaloids isolated from Streptomyces venezuelae ISP5230, exhibit cytotoxic activity against multidrug-resistant breast cancer cells. We have previously achieved the total synthesis of jadomycins using the direct arylation of juglone as a key step. In this study, we achieved the total synthesis of jadomycin T and jadomycin aglycons using L-threonine and 1-amino-2-propanol as nitrogen sources. Additionally, we evaluated the cytotoxic activity of eight compounds, including glycosides, jadomycin T, and their corresponding aglycons, in eight types of tumor cells. The evaluated jadomycins tended to exhibit stronger cytotoxic activity as aglycons than as glycosides. Although the presence of a 1,3-oxazolidine ring derived from an amino acid was not essential, the presence of the 1,3-oxazolidine ring showed strong activity when the ring had a carboxyl group. Furthermore, compared to the non-natural isomer at a different position on the phenolic hydroxyl group, the naturally occurring phenanthroviridin aglycon exhibited stronger cytotoxic activity. In addition, this study suggests that jadomycins may become lead compounds for the treatment of brain tumors; however, further studies on their ability to penetrate the blood–brain barrier are required.