Bicyclization Involving Pseudo-Intramolecular Imination with Diamines

α-Nitro-δ-keto nitriles and α-nitro-δ-keto ester were readily converted to diazabicyclo compounds having vicinal functionality upon treatment with diamines. The keto nitrile attracts the diamine nearby to an acidic hydrogen to cause the pseudo-intramolecular imination which proceeds efficiently without any catalyst at room temperature

One-step synthesis of differently bis-functionalized isoxazoles by cycloaddition of carbamoylnitrile oxide with β-keto esters

A new protocol for synthesizing different functionalized isoxazoles is provided. Carbamoylnitrile oxide generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with 1,3-dicarbonyl compounds in the presence of magnesium acetate that formed magnesium enolatein situ. Although electron-deficient trifluoroacetoacetate did not undergo this cycloaddition under the same conditions, conversion to sodium enolate furnish the corresponding bis-functionalized trifluoromethylisoxazole. The DFT calculations using B3LYP 6-31G+(d,p) also supported the aforementioned reactivity

A formal total synthesis of the telomerase inhibitor dictyodendrin B

A formal synthesis of the telomerase inhibitory marine pyrrolocarbazole alkaloid dictyodendrin B is described. The key features are consecutive palladium-catalyzed cross-coupling reactions and intramolecular reductive coupling reaction to construct the pyrrolo[2,3-c]carbazole framework

Drug retention of biologics and Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study

OBJECTIVES: This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis. METHODS: The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation. RESULTS: TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55). CONCLUSIONS: TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.Ebina K., Etani Y., Maeda Y., et al. Drug retention of biologics and Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study. RMD open 9, (2023); https://doi.org/10.1136/rmdopen-2023-003160

Algicidal activity of polyunsaturated fatty acids derived from Ulva fasciata and U. pertusa (Ulvaceae, Chlorophyta) on phytoplankton

Isolation of algicidal compounds from Ulva fasciata revealed that the algicidal substances were the polyunsaturated fatty acids (PUFAs) as hexadeca-4,7,10,13-tetraenoic acid (HDTA) C16:4 n-3, octadeca-6,9,12,15- tetraenoic acid (ODTA) C18:4 n-3, α-linolenic acid (ALA) C18:3 n-3 and linoleic acid (LA) C18:2 n-6. The fatty acid composition of four species of Ulvaceae (U. fasciata, U. pertusa, U. arasakii and U. conglobota) was analyzed by capillary gas chromatography to investigate the relationship with the algicidal activity. The results indicate that highly algicidal species, U. fasciata and U. pertusa, showed higher contents of C16:4 n-3, C18:3 n-3, and C18:4 n-3. Concentrations of these PUFAs released from the seaweed in the culture medium were also analyzed. These PUFAs were found to be significantly active against Chattonella antiqua, C. marina, Fibrocapsa japonica, Heterosigma akashiwo, Karenia mikimotoi, moderately effective against Heterocapsa circularisquama, Prorocentrum minimum, P. sigmoides, Scrippsiella trochoidea, whereas low effective against Alexandrium catenella and Cochlodinium polykrikoides. It is suggested that the PUFAs are useful mitigation agents to remove several harmful effects without causing detrimental effects on surrounding marine living organisms

Precise Synthesis of Macromolecular Architectures by Novel Iterative Methodology Combining Living Anionic Polymerization with Specially Designed Linking Chemistry

This article reviews the development of a novel all-around iterative methodology combining living anionic polymerization with specially designed linking chemistry for macromolecular architecture syntheses. The methodology is designed in such a way that the same reaction site is always regenerated after the polymer chain is introduced in each reaction sequence, and this “polymer chain introduction and regeneration of the same reaction site” sequence is repeatable. Accordingly, the polymer chain can be successively and, in principle, limitlessly introduced to construct macromolecular architectures. With this iterative methodology, a variety of synthetically difficult macromolecular architectures, i.e., multicomponent μ-star polymers, high generation dendrimer-like hyperbranched polymers, exactly defined graft polymers, and multiblock polymers having more than three blocks, were successfully synthesized

Precise Synthesis of New Exactly Defined Graft Copolymers Made up of Poly(alkyl methacrylate)s by Iterative Methodology Using Living Anionic Polymerization

An iterative methodology using living anionic polymerization with a 1,1-diphenylethylene disubstituted with trimethylsilyl (TMS) and <i>tert</i>-butyldimethylsilyl (TBS) ethers has been developed in order to synthesize new exactly defined graft copolymers made up of poly­(alkyl methacrylate)­s. During each reaction sequence, the TMS and TBS ethers were transformed into α-phenyl acrylate (PA) functions one by one at the different reaction stages. The first PA function derived from the TMS ether was utilized to introduce the graft chain, while the main chain with the TMS and TBS ethers was introduced via the second PA function derived from the TBS ether. Thus, the same chain-end functionalities (both TMS and TBS ethers) were reintroduced after construction of the graft unit. In practice, the reaction sequence involving “the introduction of the graft chain” and “the introduction of the main chain with the two silyl ethers” was iterated three times, leading to the synthesis of poly­(benzyl methacrylate) (PBnMA)-<i>exact graft</i>-poly­(methyl methacrylate) (PMMA) with three PMMA graft chains. Similarly, the synthesis of PBnMA-<i>exact graft</i>-poly­(2-vinylpyridine) (P2VP) with two P2VP graft chains was successfully carried out. With the use of the α,ω-chain-end-difunctionalized PBnMA as the starting material, two graft units could be constructed at the same time by iterating the reaction sequence once. The graft copolymers with up to six graft chains were obtained by only three repeated reaction sequences. Thus, the reaction steps could be significantly reduced. The graft copolymers synthesized in this study were perfectly controlled in structure from a viewpoint of the following three parameters defining the structure of the graft copolymer: (1) molecular weight of the main chain, (2) molecular weights of the graft chains, and (3) number and placement of the graft chains. Furthermore, these three parameters can also be intentionally changed as required