A simple synthesis of trans -3,4,5-trimethoxycinnamamides and evaluation of their biologic activity
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Med Chem Res (2013) 22:4615–4621 DOI 10.1007/s00044-012-0415-1
ORIGINAL RESEARCH
A simple synthesis of trans-3,4,5-trimethoxycinnamamides and evaluation of their biologic activity Jae-Chul Jung • Dongguk Min • Heena Lim • Sohyeon Moon Mankil Jung • Seikwan Oh
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Received: 6 March 2012 / Accepted: 11 December 2012 / Published online: 17 January 2013 Ó Springer Science+Business Media New York 2013
Abstract A simple synthesis and biologic evaluation of trans-3,4,5-trimethoxycinnamamides 10a–e and 11 as novel antinarcotic agents is described. The synthetic key strategies involve condensation reaction and coupling reaction to generate trans-3,4,5-trimethoxycinnamamides 10a–e and 11. They were evaluated for free radical scavenging, inhibitory action for neurotoxicity in cultured neurons, and antinarcotic activity in mice. It was found that compounds 10a, 10d, and 10e displayed significant inhibitory action of the glutamate-induced neurotoxicity and 10a–e and 11 showed high antinarcotic activity in mice. Keywords Trans-3,4,5-trimethoxycinnamamides Condensation reaction Coupling reaction Antineurotoxicity Free radical scavenging Antinarcotic activity
Introduction Many methoxycinnamic acids and their derivatives have been of interest for their antibacterial (Srivastava et al., 2007), antiviral (King et al., 2009; Lee et al., 2007), anti-inflammatory (Chen et al., 2007), antitumor (Fong et al., 2008), J.-C. Jung H. Lim S. Moon S. Oh (&) Department of Neuroscience and TIDRC, School of Medicine, Ewha Womans University, Seoul 158-710, Korea e-mail: [email protected] J.-C. Jung e-mail: [email protected] D. Min M. Jung Department of Chemistry, Yonsei University, Seoul 120-749, Korea e-mail: [email protected]
antioxidant (Carlotti et al., 2008), and antipyretic effect (Sultana et al., 2005; Kurokawa et al., 1998). In particular, trans-cinnamic acids and its derivatives are very effective to modulate central nervous system (CNS) including attention deficit hyperactivity disorder (ADHD), narcolepsy effects (Nardi et al., 2008), and antidepressant-like effects were related to sedative activity by suppressing norepinephrine content in locus coeruleus (Kawashima et al., 2004) (Fig. 1). 3,4,5-Trimethoxycinnamic acid (TMCA) is a component of the root of Polygala tenuifolia WILLLDENOW (polygalaceae) and its extract was used as a sedative in Japanese traditional Kampo medicine (Kawashima et al., 2004). The Kawashima group studied the effect of TMCA on stress-induced corticotrophin-releasing hormone (CRH) release and found that TMCA exhibits sedative effects by suppressing norepinephrine (NE) content in the locus coeruleus (LC) (Kawashima et al., 2004). Hyperactivity of LC neurons is an important component of opiate withdrawal. Opiate withdrawal syndrome is mediated by an excitatory amino acid (glutamate) input to the LC and causes hyperactivity in the LC region (Akaoka and AstonJones, 1993). To determine the development of morphine dependence in mice or rats, naloxone (opioid receptor antagonist) was injected and
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