Left lateral prefrontal activity reflects a change of behavioral tactics to cope with a given rule: An fNIRS study

Rules prescribe human behavior and our attempts to choose appropriate behavior under a given rule. Cognitive control, a mechanism to choose and evaluate actions under a rule, is required to determine the appropriate behavior within the limitations of that rule. Consequently, such cognitive control increases mental workload. However, the workload caused by a cognitive task might be different when an additional rule must be considered in choosing the action. The present study was a functional near-infrared spectroscopy (fNIRS) investigation of an experimental task, in which the difficulty of an operation and existence of an additional rule were manipulated to dissociate the influence of that additional rule on cognitive processing. Twenty healthy Japanese volunteers participated. The participants performed an experimental task, in which the player caught one of five colored balls from the upper part of a computer screen by operating a mouse. Four task conditions were prepared to manipulate the task difficulty, which was defined in terms of operational difficulty. In turn, operational difficulty was determined by the width of the playable space and the existence of an additional rule, which reduced the score when a red ball was not caught. The 52-channel fNIRS data were collected from the forehead. Two regions of interest (ROIs) associated with the bilateral lateral prefrontal cortices (LPFCs) were determined, and a three-way repeated-measures analysis of variance (ANOVA) was performed using the task-related signal changes from each ROI. The fNIRS results revealed that bilateral LPFCs showed large signal changes with the increase in mental workload. The ANOVA showed a significant interaction between the existence of an additional rule and the location of the ROIs; that is, the left lateral prefrontal area showed a significant increase in signal intensity when the additional rule existed, and the participant occasionally decided to avoid catching a ball to successfully catch the red-colored ball. Thus, activation of the left LPFC corresponded more closely to the increase in cognitive control underlying the behavioral change made to cope with the additional rule

Structure-Activity Relationships of the Antitumor C5-Curcuminoid GO-Y030

1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (2) was isolated from Curcuma domestica as a curcumin (1)-related compound, which we named C5-curcumin. Intrigued by the potent antitumor activity of C5-curcumin (2)-related 1,5-bisaryl-1,4-pentadiene-3-ones [bis(arylmethylidene)acetones, termed C5-curcuminoids], we previously conducted a structure–activity relationship study of C5-curcuminoids and showed that highly active GO-Y030 [1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one (4)] is the most promising antitumor compound. In this study, a panel of C5-curcuminoids based on GO-Y030, consisting of 30 new and 10 known compounds, was synthesized to elucidate in detail which moiety of GO-Y030 is significant for antitumor activity. The results confirmed that both the cross-conjugated dienone moiety and the 3,5-bis(methoxymethoxy) substituent are important for the antitumor activity

Design, Synthesis, and Evaluation of Trivalent PROTACs Having a Functionalization Site with Controlled Orientation

Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 (1) in complex with human VHL and BRD4BD2, we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 (1) could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, 2a-c and 3a-c, by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (1 or 2). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 (2a), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 (1). Based on the structure of 2a, we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, 15a-15d, having a tert-butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 (15c) retained a level of BRD4 depletion activity similar to that of 2a without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 (1). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications

Third Generation Photo-Cross-Linked Small-Molecule Affinity Matrix: A Photoactivatable and Photocleavable System Enabling Quantitative Analysis of the Photo-Cross-Linked Small Molecules and Their Target Purification

The third generation of photoactivatable beads designed to capture bioactive small molecules in a chemo- and site-nonselective manner upon irradiation at 365 nm of UV light and release them as coumarin conjugates after exposure to UV light of 302 nm is described. These photoactivatable and photocleavable beads enable quantification of the amount and distribution of immobilized small molecules prior to the pull-down experiments to identify target protein(s) for the immobilized small molecules. The newly developed system was then used to analyze the functional group compatibility of the photo-cross-linking technology as well as the preferable nature of small molecules to be immobilized. As a result, compounds having a hydroxyl group, carboxylic acid, or aromatic ring were shown to give multiple conjugates, indicating that these compounds are well compatible with the photoactivatable beads system