Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine†A.

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Electrical stimulation characteristics of denervated orbicularis oculi muscle.

This research is to study the electrical stimulation characteristics of orbicularis oculi muscle and the characteristics of the mechanical contraction. We observed the stimulus current diffusion regularity and its relationship with mechanical contraction in the orbicularis oculi muscle using an electrode gathering line. Under different stimulus intensities of 2 or 4 mA, the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. In addition, current conduction across the muscle fiber was studied. Under different stimulus intensities of 2 or 4 mA, it was found that the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. The transverse current reached a maximum 4 mA range, and increasing the current intensity did not increase the propagation range. Under different stimulation intensities, the larger the stimulus intensity, the greater is the potential change and the faster is the attenuation. Longitudinal current, even in the range of 6 mm, can still record electrical activity. While a transverse current diffuser has a maximum range of 4 mm, increasing the current intensity does not increase the propagation range.

Structure units oriented approach towards collective synthesis of sarpagine-ajmaline-koumine type alkaloids.

Sarpagine-Ajmaline-Koumine type monoterpenoid indole alkaloids represent a fascinating class of natural products with polycyclic and cage-like structures, interesting biological activities, and related biosynthetic origins. Herein we report a unified approach towards the asymmetric synthesis of these three types of alkaloids, leading to a collective synthesis of 14 natural alkaloids. Among them, akuammidine, 19-Z-akuammidine, vincamedine, vincarine, quebrachidine, vincamajine, alstiphylianine J, and dihydrokoumine are accomplished for the first time. Features of our synthesis are a new Mannich-type cyclization to construct the key indole-fused azabicyclo[3.3.1]nonane common intermediate, a SmI2 mediated coupling to fuse the aza-bridged E-ring, stereoselective olefinations to install either the 19-E or 19-Z terminal alkenes presented in the natural alkaloids, and an efficient iodo-induced cyclization to establish the two vicinal all-carbon quaternary centers in the Koumine-type alkaloids.

Design, Synthesis, and Anticancer Activity of Novel Trimethoxyphenyl-Derived Chalcone-Benzimidazolium Salts.

A series of novel trimethoxyphenyl-derived chalcone-benzimidazolium salts were synthesized. The biological properties of the compounds were screened in vitro against five different human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole ring as well as the 2-naphthylmethyl, 4-methylbenzyl, or 2-naphthylacyl substituent at position-3 of the benzimidazole ring was important to the cytotoxic activity. Notably, (E)-5,6-dimethyl-3-(naphthalen-2-ylmethyl)-1-(3-(4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenoxy)propyl)-1H-benzo[d]imidazol-3-ium bromide (7f) was more selective to HL-60, MCF-7, and SW-480 cell lines with IC50 values 8.0-, 11.1-, and 5.8-fold lower than DDP. Studies of the antitumor mechanism of action showed that compound 7f could induce cell-cycle G1 phase arrest and apoptosis in SMMC-7721 cells.

Direct electrodeposition of Graphene enhanced conductive polymer on microelectrode for biosensing application.

Engineering of neural interface with nanomaterials for high spatial resolution neural recording and stimulation is still hindered by materials properties and modification methods. Recently, poly(3,4-ethylene-dioxythiophene) (PEDOT) has been widely used as an electrode-tissue interface material for its good electrochemical property. However, cracks and delamination of PEDOT film under pulse stimulation are found which restrict its long-term applications. This paper develops a flexible electrochemical method about the co-deposition of graphene with PEDOT on microelectrode sites to enhance the long-term stability and improve the electrochemical properties of microelectrode. This method is unique and profound because it co-deposits graphene with PEDOT on microelectrode sites directly and avoids the harmful post reduction process. And, most importantly, significantly improved electrochemical performances of the modified microelectrodes (compared to PEDOT-GO) are demonstrated due to the large effective surface area, good conductivity and excellent mechanical property of graphene. Furthermore, the good mechanical stability of the composites is verified by ultrasonication and CV scanning tests. In-vivo acute implantation of the microelectrodes reveals the modified microelectrodes show higher recording performance than the unmodified ones. These findings suggest the composites are excellent candidates for the applications of neural interface.

Progress in Research of Flexible MEMS Microelectrodes for Neural Interface.

With the rapid development of Micro-electro-mechanical Systems (MEMS) fabrication technologies, many microelectrodes with various structures and functions have been designed and fabricated for applications in biomedical research, diagnosis and treatment through electrical stimulation and electrophysiological signal recording. The flexible MEMS microelectrodes exhibit excellent characteristics in many aspects beyond stiff microelectrodes based on silicon or metal, including: lighter weight, smaller volume, better conforming to neural tissue and lower fabrication cost. In this paper, we reviewed the key technologies in flexible MEMS microelectrodes for neural interface in recent years, including: design and fabrication technology, flexible MEMS microelectrodes with fluidic channels and electrode⁻tissue interface modification technology for performance improvement. Furthermore, the future directions of flexible MEMS microelectrodes for neural interface were described, including transparent and stretchable microelectrodes integrated with multi-functional aspects and next-generation electrode⁻tissue interface modifications, which facilitated electrode efficacy and safety during implantation. Finally, we predict that the relationships between micro fabrication techniques, and biomedical engineering and nanotechnology represented by flexible MEMS microelectrodes for neural interface, will open a new gate to better understanding the neural system and brain diseases.

Enhanced Flexible Tubular Microelectrode with Conducting Polymer for Multi-Functional Implantable Tissue-Machine Interface.

Implantable biomedical microdevices enable the restoration of body function and improvement of health condition. As the interface between artificial machines and natural tissue, various kinds of microelectrodes with high density and tiny size were developed to undertake precise and complex medical tasks through electrical stimulation and electrophysiological recording. However, if only the electrical interaction existed between electrodes and muscle or nerve tissue without nutrition factor delivery, it would eventually lead to a significant symptom of denervation-induced skeletal muscle atrophy. In this paper, we developed a novel flexible tubular microelectrode integrated with fluidic drug delivery channel for dynamic tissue implant. First, the whole microelectrode was made of biocompatible polymers, which could avoid the drawbacks of the stiff microelectrodes that are easy to be broken and damage tissue. Moreover, the microelectrode sites were circumferentially distributed on the surface of polymer microtube in three dimensions, which would be beneficial to the spatial selectivity. Finally, the in vivo results confirmed that our implantable tubular microelectrodes were suitable for dynamic electrophysiological recording and simultaneous fluidic drug delivery, and the electrode performance was further enhanced by the conducting polymer modification.

Fabrication and electrochemical comparison of SIROF-AIROF-EIROF microelectrodes for neural interfaces.

Iridium oxide has been widely used in neural recording and stimulation due to its good stability and large charge storage capacity (CSC). In general, the iridium oxide film used in the electrophysiological application can be grouped into three principal classifications: sputtering iridium oxide film (SIROF), activated iridium oxide film (AIROF) and electrodeposited iridium oxide film (EIROF). Although these kinds of iridium oxide all can remarkably reduce the impedance and increase the CSC of the microelectrode, they also exhibit markedly differences in electrochemical performances. After activation, the CSC of EIROF is 68.20 mC/cm(2), which is 88.7 % larger than that of the SIROF and 67.6 % larger than that of the AIROF. The impedance at 1 kHz of the three kinds of iridium oxide microelectrode is around 4000 ohm, it is acceptable for the neural interface application. The phase at 1 kHz of the AIROF microelectrode is the largest which is -6.1 degree, about 22.6 % of the SIROF and 44.5 % of the EIROF.

Flexible intramuscular micro tube electrode combining electrical and chemical interface.

With the rapidly developed micromachining technology, various kinds of sophisticated microelectrodes integrated with micro fluidic channels are design and fabricated for not only electrophysiological recording and stimulation, but also chemical drug delivery. As many efforts have been devoted to develop rigid microprobes for neural research of brain, few researchers concentrate on fabrication of flexible microelectrodes for intramuscular electrophysiology and chemical interfacing. Since crude wire electrodes still prevail in functional electrical stimulation (FES) and electromyography (EMG) recording of muscle, here we introduce a flexible micro tube electrode combining electrical and chemical pathway. The proposed micro tube electrode is manufactured based on polymer capillary, which provide circumferential electrode site contacting with electro-active tissue and is easy to manufactured with low cost.

Poly(3,4-ethylenedioxythiophene)/graphene oxide composite coating for electrode-tissue interface.

Owing to interacting with the living tissue directly, the electrode-tissue interface largely determines the performance of the whole bioelectronics devices. The miniaturization of biomedical electronic components requires interface materials to possess properties including excellent electrical performance, good biocompatibility and compatibility with microelectronic fabrication process. Considering the unique characteristics and wide applications in biomedical domain of conducting polymer and graphene, composite film consists of poly(3,4-ethylenedioxythiophene) (PEDOT) and graphene oxide (GO) is proposed as electrode-tissue interface in this work. The facilely electrochemically synthesized PEDOT/GO coating on microelectrodes shows low impedance, high charge storage capacity and good biocompatibility to act as electrode-tissue interface. As a result, the composite film is a potential biomaterial as electrode-tissue interface for tissue engineering and further implantable electrophysiological devices.

Graphene oxide doped conducting polymer nanocomposite film for electrode-tissue interface.

One of the most significant components for implantable bioelectronic devices is the interface between the microelectrodes and the tissue or cells for disease diagnosis or treatment. To make the devices work efficiently and safely in vivo, the electrode-tissue interface should not only be confined in micro scale, but also possesses excellent electrochemical characteristic, stability and biocompatibility. Considering the enhancement of many composite materials by combining graphene oxide (GO) for its multiple advantages, we dope graphene oxide into poly(3,4-ethylenedioxythiophene) (PEDOT) forming a composite film by electrochemical deposition for electrode site modification. As a consequence, not only the enlargement of efficient surface area, but also the development of impedance, charge storage capacity and charge injection limit contribute to the excellent electrochemical performance. Furthermore, the stability and biocompatibility are confirmed by numerously repeated usage test and cell proliferation and attachment examination, respectively. As electrode-tissue interface, this biomaterial opens a new gate for tissue engineering and implantable electrophysiological devices.