Total synthesis and biomimetic studies of nine-membered enediynes

The kedarcidin and C1027 chromophores are formidable targets of total synthesis. During our 20-year study of these nine-membered enediyne chromophores, several powerful, yet chemoselective methods have been developed: stereoselective epoxyalkyne formation, atropselective Pd/Cu-Sonogashira coupling, 2-deoxy-α-glycosylation, CeX3-mediated enediyne cyclisation, and SmI2-based reductive olefination. Besides their total syntheses, application of these methods to the biomimetic study of the putative enediyne-precursors of the cyanosporasides, sporolides, and fijiolides will be presented. In particular, we disclose biomimetic evidence of a p-benzyne diradical species reacting in either a radical mode (hydrogen abstraction) or ionic mode (chloride attack) at the same sterically exposed site, leading to either monochlorinated cyanosporaside A/F or cyanosporaside B–E, respectively. The ionic monochlorination of the cycloaromatized p-benzyne of the C1027 enediyne core to generate the fijiolide aglycon framework will also be presented

Ecdysone-dependent and ecdysone-independent programmed cell death in the developing optic lobe of Drosophila

AbstractThe adult optic lobe of Drosophila develops from the primordium during metamorphosis from mid-3rd larval stage to adult. Many cells die during development of the optic lobe with a peak of the number of dying cells at 24h after puparium formation (h APF). Dying cells were observed in spatio-temporal specific clusters. Here, we analyzed the function of a component of the insect steroid hormone receptor, EcR, in this cell death. We examined expression patterns of two EcR isoforms, EcR-A and EcR-B1, in the optic lobe. Expression of each isoform altered during development in isoform-specific manner. EcR-B1 was not expressed in optic lobe neurons from 0 to 6h APF, but was expressed between 9 and 48h APF and then disappeared by 60h APF. In each cortex, its expression was stronger in older glia-ensheathed neurons than in younger ones. EcR-B1 was also expressed in some types of glia. EcR-A was expressed in optic lobe neurons and many types of glia from 0 to 60h APF in a different pattern from EcR-B1. Then, we genetically analyzed EcR function in the optic lobe cell death. At 0h APF, the optic lobe cell death was independent of any EcR isoforms. In contrast, EcR-B1 was required for most optic lobe cell death after 24h APF. It was suggested that cell death cell-autonomously required EcR-B1 expressed after puparium formation. βFTZ-F1 was also involved in cell death in many dying-cell clusters, but not in some of them at 24h APF. Altogether, the optic lobe cell death occurred in ecdysone-independent manner at prepupal stage and ecdysone-dependent manner after 24h APF. The acquisition of ecdysone-dependence was not directly correlated with the initiation or increase of EcR-B1 expression

A Convergent Total Synthesis of the Kedarcidin Chromophore: 20-Years in the Making

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we 19 describe a viable synthesis of this highly unstable natural product. This entailed the early 20 introduction and gram-scale synthesis of 2-deoxysugar conjugates of both L-mycarose and L21 kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an 22 epoxyalkyne; (2) -selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) 23 and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis24 configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; 25 (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine26 membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive 27 olefination and global HF-deprotection end-game. The longest linear sequence from gram28 scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained 29 for the first tim

Mechanical stability of orthodontic miniscrew depends on a thread shape

Background/purpose: Primary stability of orthodontic miniscrew system is of great importance in maintaining stable anchorage during a treatment period. Thus, this study aimed to examine whether the thread shape of orthodontic miniscrew had an effect on its mechanical stability in bone. Materials and methods: Three different types of miniscrews (type A and B with a regular thread shape; type C with a novel thread shape) were placed in artificial bone block with different artificial cortical bone thickness of 1.5, 2.0 and 3.0 mm. Values of maximum insertion torque (MIT), removal torque (RT), torque ratio (TR), screw mobility, static stiffness (K), dynamic stiffness (K∗) and energy dissipation (tan δ) ability were assessed for each miniscrew system. Results: The MIT, RT, TR and K of type C miniscrew were significantly greater than those of type A and B miniscrews when the miniscrews were placed in the thinner artificial bone. Furthermore, the TR value of type C miniscrew was more than 1, indicating the MRT value was larger than the MIT value in the novel miniscrew. The values of K∗ and tan δ were almost similar among the three types of miniscrews. Conclusion: The miniscrew with a novel thread shape showed a higher initial stability compared to those with a regular thread shape. Thus, in order to obtain a sufficient initial stability, it is important to select the type of screw thread that is appropriate for the thickness of the cortical bone

歯科矯正用アンカースクリューおよび周囲骨の応力分布に及ぼす埋入深さの影響 : 有限要素法による解析

We aimed to elucidate stress distribution in miniscrews and the surrounding bone when miniscrews inserted at different depths were implanted vertically or obliquely. The distributions of the equivalent stress on the screw surface and the minimum principal stress in the surrounding bone were calculated using finite element models. When the miniscrews were inserted vertically and obliquely, screw head displacement, greatest equivalent stress on the miniscrew surface, and absolute value of minimum principal stresses in the surrounding bone decreased with increasing insertion depth. Stresses in the obliquely inserted miniscrew with upward traction were smaller than in other insertion conditions, irrespective of insertion depth. With the application of orthodontic force, stress distribution around the miniscrew and surrounding bone is closely related to the insertion depth and insertion angle, which mutually affect each other. In particular, the obliquely inserted miniscrew with upward traction might be the most secure against screw failure and fracture

Polarity-Driven Isomerization of a Hydroxynaphthalimide-Containing Spiropyran at Room Temperature

Design of spiropyrans showing spontaneous isomerization driven by the polarity of solvents is an important consideration for the synthesis of optical sensory materials. Although some spiropyrans undergo polarity-driven isomerization, they must be heated owing to the high activation energy required for isomerization. In this study, we describe that a spiropyran containing a hydroxynaphthalimide unit (1) exhibits a polarity-driven isomerization at room temperature. It exists as a colorless spirocyclic (SP) form in less polar solvents but is isomerized to a colored merocyanine (MC) form in polar solvents. The equilibrium amount of the MC form increases with an increase in the polarity of solvents. The MC form involves two resonance structuresthe quinoidal and zwitterionic forms. In polar media, the zwitterionic form dominates mainly owing to solvation by polar molecules. Solvation stabilizes the negative charge of the zwitterionic form and decreases its ground state energy, thereby enhancing SP → MC isomerization. The SP ⇌ MC isomerization terminates within barely 30 s even at room temperature because the naphthol moiety with high π-electron density lowers the activation energy for the rate-determining rotational step