In the present work, the [3 + 2] cycloaddition reaction of 5,5-dimethyl-1-pyrroline N-oxide (Nit-5) and 2-cyclopentenone (CPN-6), experimentally reported by Tamura et al., was theoretically studied using the newly introduced molecular electron density theory (MEDT). Based on the experimental findings, this reaction takes place in an O3-C4 regio- and an exo-stereospecific fashion to give corresponding [3 + 2] exo cycloadduct as the sole product. The results of the potential energy surface analysis indicated that the experimentally reported product is more favorable both thermodynamically and kinetically relative to other possible adducts. In complete agreement with the experimental outcomes, the conceptual density functional theory reactivity indices explained the reactivity and regioselectivity of the reaction. Calculation of global electron density transfer of the energetically most preferred transition state indicated that the electron density fluxes from Nit-5 as a nucleophilic species toward CPN-6 as an electrophilic species. Analysis of the molecular electrostatic potential map of the most favorable transition state showed that approach of Nit-5 and CPN-6 locates the oppositely charged regions over each other leading to attractive forces between two reagents rationalizing the exo stereoselectivity predominance. The molecular mechanism of the reactions was specified using electron localization function analysis over some relevant points along the intrinsic reaction coordinate profile of the most favorable transition state and the results indicated that this zwitterionic-type [3 + 2] cycloaddition reaction proceeds through a two-stage one-step mechanism. In fact, while the O3-C4 single bond is initialy formed between two fragments through donation of some electron density from the O3 oxygen lone electron-pairs of Nit-5 toward the C4 carbon atom of CPN-6, the delayed C1-C5 single bond begins to form via C1- to -C5 coupling of pseudodiracal centers created on theses atoms over the course of reaction.

01 Sep 2017·Advanced ScienceQ1 · MATERIALS SCIENCE

Ultrasmall Conjugated Polymer Nanoparticles with High Specificity for Targeted Cancer Cell Imaging

Q1 · MATERIALS SCIENCE

ArticleOA

Author: Tomczak, Nikodem ; Mao, Duo ; Liu, Bin ; Liu, Jie ; Feng, Guangxue ; Liu, Rongrong

Fluorescent and biocompatible organic nanoparticles have attracted great interest in cancer detection and imaging, but the nonspecific cellular uptake has limited the detection specificity and sensitivity. Herein, the authors report the ultrasmall conjugated polymer nanoparticles (CPNs) with bright far‐red/near‐infrared emission for targeted cancer imaging with high specificity. The sizes of the ultrasmall CPNs are around 6 nm (CPN6), while large CPNs show sizes around 30 nm (CPN30). Moreover, CPN6 exhibits largely improved fluorescence quantum yield (η) of 41% than CPN30 (25%). Benefiting from the ultrasmall size, bare CPN6 shows largely suppressed nonspecific cellular uptake as compared to CPN30, while cyclic arginine‐glycine‐aspartic acid (cRGD) functionalized CPN6 (cRGD‐CPN6) possesses excellent selectivity toward αvβ3 integrin overexpressed MDA‐MB‐231 cells over other cells in cell mixtures. The faster body clearance of CPN6 over CPN30 indicates its greater potentials as a noninvasive nanoprobe for in vivo and practical applications.

01 Dec 2012·Free Radical Biology and MedicineQ2 · MEDICINE

A novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide, selectively protects against oxidative stress-induced cell death by activating the Nrf2–ARE pathway: Therapeutic implications for ALS

Q2 · MEDICINE

Article

Author: Takuya Kanno ; Joh-E Ikeda ; Noriaki Hirayama ; Fumihito Yoshii ; Kaori Yasutake ; Yoshiko Yanagisawa ; Shinji Hadano ; Kazunori Tanaka

Antioxidant defense is crucial in restoring cellular redox homeostasis. Recent findings have suggested that oxidative stress plays pivotal roles in the pathogenesis of many neurodegenerative diseases. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of such disorders. In this study, we employed a novel ligand-based virtual screening system and identified a novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide (CPN-9), which selectively suppressed oxidative stress-induced cell death in a cell-type-independent manner. CPN-9 upregulates NF-E2-related factor 2 (Nrf2), a key transcriptional regulator of the expression of phase II detoxification enzymes and antioxidant proteins, and Nrf2-regulated factors such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase modifier subunit (GCLM). The CPN-9-mediated upregulation of HO-1, NQO1, and GCLM was abolished by Nrf2 knockdown. Moreover, the antioxidant N-acetylcysteine reduced the protective effect of CPN-9 against oxidative stress-induced cell death with concomitant diminishing of Nrf2 nuclear translocation. These results indicate that CPN-9 exerts its activity via the reactive oxygen species-dependent activation of the Nrf2 signaling pathway in cultured cells. It is noteworthy that the postonset systemic administration of CPN-9 to a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene sustained motor functions and delayed disease progression after onset. Collectively, CPN-9 is a novel Nrf2 activator and a neuroprotective candidate for the treatment of neurodegenerative diseases, including ALS.

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Indication	Highest Phase	Country/Location	Organization	Date
Motor Neuron Disease	Discovery	JP	NewGen Pharma Inc.	-

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