- Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram-Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury
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Traumatic brain injury (TBI) is a prevalent public healthcare concern frequently instigated by mechanical shock, traffic, or violence incidents, leading to permanent nerve damage, and there is no ideal treatment for it yet. In this study, a series of Rolipram-Tranilast hybrids were designed and synthesized. The neuroprotective activities of the Rolipram-Tranilast hybrids were evaluated both in vitro and in vivo. Compound 5 has been identified as the strongest neuroprotective molecule among the series with robust anti-oxidant and anti-inflammatory potentials. Compound 5 significantly increased the heme oxygenase-1 (HO-1) levels and the phosphorylated cAMP response elements binding protein (p-CREB) while it down-regulated phosphodiesterase-4 B (PDE4B) expression in vitro. Furthermore, compound 5 remarkably attenuated TBI and had a good safety profile in mice. Taken together, our findings suggested that compound 5 could serve as a novel promising lead compound in the treatment of TBI and other central nervous system (CNS) diseases associated with PDE4B and oxidative stress.
- Chen, Chen,Deng, Xiaobing,Han, Yifan,He, Xixin,Liang, Jinhao,Lu, Junfeng,Maddili, Swetha K.,Mak, Marvin Sh,Pi, Rongbiao,Tsim, Karl W. K.,Zhu, Zeyu
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- Synthesis, biological evaluation, and molecular modeling of new 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2- oxoethyl) oxime (GEBR-7b) related phosphodiesterase 4D (PDE4D) inhibitors
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A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.
- Brullo, Chiara,Massa, Matteo,Rocca, Massimo,Rotolo, Chiara,Guariento, Sara,Rivera, Daniela,Ricciarelli, Roberta,Fedele, Ernesto,Fossa, Paola,Bruno, Olga
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p. 7061 - 7072
(2014/11/07)
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- Enantioselective Michael additions of nitromethane by a catalytic double activation method using chiral Lewis acid and achiral amine catalysts
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Reactions of nitromethane with 1-(2-alkenoyl)-3,5-dimethylpyrazoles can be effectively catalyzed by R,R-DBFOX/Ph·Ni(ClO4)2·3H2O and achiral amine bases, each in a catalytic loading of 10 mol %, to give 1-(3-substituted 4-n
- Itoh, Kennosuke,Kanemasa, Shuji
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p. 13394 - 13395
(2007/10/03)
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- Synthesis of the novel antidepressant (R)-(-)-Rolipram
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Enantioselective synthesis of (R)-Rolipram 1 has been achieved through a conjugate addition of cyanide to enantiomerically pure 2-(2-aryl ethenyl)oxazoline 2, followed by selective reduction of the adduct with NaBH4-NiCl2.
- Langlois, Nicole,Wang, Hai-Shan
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p. 3133 - 3144
(2007/10/03)
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