Synthesis and radical-scavenging activity of a dimethyl catechin analogue Kohei Imai a , Ikuo Nakanishi b , Akiko Ohno c , Masaaki Kurihara c , Naoki Miyata d , Ken-ichiro Matsumoto b , Asao Nakamura a , Kiyoshi Fukuhara e,⇑ a Department of Applied Chemistry, Shibaura Institute of Technology, Fukasaku, Minuma-ku, Saitama 337-8570, Japan b Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan c Division of Organic Chemistry, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan d Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Aichi 467-8603, Japan e School of Pharmacy, Showa University, Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan article info Article history: Received 6 January 2014 Revised 10 March 2014 Accepted 12 March 2014 Available online 20 March 2014 Keywords: Antioxidant Synthetic antioxidant Catechin Radical scavenging abstract Catechin analogue 1 with methyl substituents ortho to the catechol hydroxyl groups was synthesized to improve the antioxidant ability of (+)-catechin. The synthetic scheme involved a solid acid catalyzed Friedel–Crafts coupling of a cinnamyl alcohol derivative to 3,5-dibenzyloxyphenol followed by hydroxyl- ation and then cyclization through an intermediate orthoester. The antioxidative radical scavenging activity of 1 against galvinoxyl radical, an oxyl radical, was found to be 28-fold more potent than (+)-catechin. Ó 2014 Elsevier Ltd. All rights reserved. Among natural bioactive compounds distributed in fruits, vegetables, and beverages of plant origin, phenolic antioxidants (ArOH), such as flavonoids, tocopherol, and resveratrol, are widely recognized for their biological and pharmacological effects that include anti-carcinogenic, anti-cardiovascular anti-neurodegener- ative, and anti-inflammatory properties. 1–4 These properties are principally attributed to the capacity of these compounds to trap reactive oxygen species and to chelate metal ions, which through the Fenton reaction could generate radicals. 5 Therefore, this so-called antioxidative ability of phenolic compounds is frequently cited as the key to their success in the prevention and/or reduction of oxidative stress-related chronic diseases and age-related disor- ders. Consideration of antioxidative ability in drug development has led to interest in improving the radical scavenging activity of phenolic compounds based on the antioxidant mechanism. 6 Antioxidant activity via the direct quenching of free radicals is expressed in two mechanisms: a one-step hydrogen atom transfer from the phenolic OH group to the free radical and a single- electron transfer from ArOH to the free radical with concomitant formation of the radical cation ArOH Å+ . 7 The former process, characterized by vitamin E, is based on the capacity of a phenol to donate a hydrogen atom to a free radical. 8 Catechin and resveratrol (see Fig. 1 for the structures) scavenge free radicals by the latter mechanism. 9,10 In this case, the ionization potential (IP) of the phenol is important for the radical scavenging efficacy. Hence, introduction of electron-donating substituents at positions ortho and/or para to the phenolic hydroxyl group would decrease the IP of ArOH, thereby enhancing the radical scavenging ability. In this regard, planar catechin analogues, in which an isopropyl fragment as electron-donor was introduced into (+)-catechin by reaction with acetone, exhibited 5-fold more potent radical scav- enging activity than (+)-catechin. 11 An epigallocatechin analogue with a similarly introduced isopropyl fragment also displayed increased radical scavenging activity. 12 In the case of ortho-alkyl substituents, the ArOH Å+ formed in the reaction with a free radical is stabilized by compensation of the electron vacancy by either an inductive effect or through hyperconjugation, resulting in improved radical scavenging ability. Resveratrol analogues with one and two methyl groups at positions ortho to the phenol hydro- xyl group showed 14- and 36-fold acceleration in the ability to scavenge free radicals, respectively. 13 The aim of the present study was to synthesize the catechin analogue 1 in which both positions ortho to the catechol hydroxyl groups were substituted with methyl groups. Compared with (+)-catechin, the dimethyl analogue of catechin showed greatly enhanced radical scavenging ability against galvinoxyl radical as a model radical for reactive oxygen species. This result indicates http://dx.doi.org/10.1016/j.bmcl.2014.03.029 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +81 3 3784 8186; fax: +81 3 3784 8252. E-mail address: fukuhara@pharm.showa-u.ac.jp (K. Fukuhara). Bioorganic & Medicinal Chemistry Letters 24 (2014) 2582–2584 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl