Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel Benzopyran and Phenylpyrazole Derivatives as Akt Inhibitors. (28th December 2014)

• Record Type: Journal Article
• Authors: Zhan, Wenhu; Lin, Sendong; Chen, Jing; Dong, Xiaowu; Chu, Jianbo; Du, Wenting
• Is Part Of: Chemical biology & drug design. Volume 85:Number 6(2015:Jun.)
• Page Start: 770
• Page End: 779
• Publication Date: 2014-12-28
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12489
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12489-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>By inspiration of good Akt1 inhibitory and cytotoxic activity of our previously screened hits <bold>1</bold> and <bold>2</bold>, a series of novel benzopyrans <bold>3a</bold>–<bold>c</bold>, <bold> 4</bold> and phenylpyrazoles <bold>5a</bold>–<bold>c</bold>, <bold> 6a</bold>–<bold>b</bold>, and <bold>7</bold> were designed, synthesized, and biologically evaluated for their in vitro Akt1 inhibitory and cytotoxic activity. The results revealed that all of these compounds showed moderate‐to‐excellent antiproliferative effects against the tested cancer cell lines (i.e. HL‐60, OVCAR, PC‐3, and HepG2). Among them, compounds <bold>3a</bold> and <bold>3c</bold> exhibited preferable Akt1 inhibitory activities (IC₅₀ of <bold>3a</bold> and <bold>3c</bold> are 6.18 and 5.28 <italic>μ</italic><sc>m</sc>, respectively), while compounds <bold>4</bold>, <bold> 5a</bold>–<bold>c</bold>, <bold> 6a</bold>–<bold>b</bold>, and <bold>7</bold> only showed weak Akt1 inhibitory activities. Consequently, we used molecular docking and dynamic simulation to propose a mode of binding between Akt1 and the <bold>3c</bold> compound.</p> </abstract>