Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells Hyuk Yoon a , Tae Woo Kim b , Soon Young Shin c , Mi Joo Park a , Yeonjoong Yong a , Dong Woon Kim d , Tasneem Islam e , Young Han Lee c , Kang-Yeoun Jung b , Yoongho Lim a,⇑ a Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea b Department of Biochemical Engineering, Gangneung-Wonju National University, Gangwon 210-702, Republic of Korea c Department of Biomedical Science and Technology, SMART-Institute of Advanced Biomedical Science, RCTC, Konkuk University, Seoul 143-701, Republic of Korea d Swine Science Division, National Institute of Animal Science, RDA, Cheonan 330-801, Republic of Korea e Department of Biological, Chemical and Physical Sciences, Roosevelt University, IL 60173, USA article info Article history: Received 26 July 2012 Revised 3 October 2012 Accepted 29 October 2012 Available online 5 November 2012 Keywords: Flavanone Naringenin Colon cancer In silico docking abstract Based on the previous result, several naringenin derivatives modified at position 7 with bulky substitu- ents were designed and synthesized, and their inhibitory effects on HCT116 human colon cancer cells were tested using a clonogenic assay. The half maximal inhibitory concentrations (IC 50 ) of five naringenin derivatives ranged between 1.20 lM and 20.01 lM which are much better than naringenin used as a con- trol. In addition, new structural modification at C-4 of flavanone results in improving both the anti-cancer effect and anti-oxidative effect. In vitro cyclin dependent kinase 2 (CDK2) binding assay was carried out based on the previous results. To elucidate the possible interaction between naringenin derivatives and CDK2, in silico docking study was performed. This result demonstrates the rationale for the different inhibitory activities of the naringenin derivatives. These findings could be used for designing cancer ther- apeutic or preventive flavanone-derived agents. Ó 2012 Elsevier Ltd. All rights reserved. Colon cancer is the fourth most commonly diagnosed malignant disease and is prevalent where the people have adopted western diets and also among the elderly. Its symptom is worsening consti- pation or bloody stool. When such symptom arises, complete treat- ment is late and 5 years survival is <60%, and thus, a periodic colonoscopy is desired. 1 Main treatment for colon cancer is sur- gery, radiation, or chemotherapy which is applied as adjuvant ther- apy in many cases. Chemotherapeutic agents such as oxaliplatin, leucovorin, and irinotecan are known, however, they are associated with severe adverse effects. Therefore, there is a need for more po- tent and less toxic drugs. 2 Flavanones, 2-phenylchroman-4-one, belong to the family of flavonoids, many of which are produced as secondary metabolites in the plant kingdom. They have three-ring skeletons, C6-C3-C6, and the rings are referred to as A-, C-, and B-rings, respectively. Their functional groups are attached to the main skeleton through oxygen or carbon linkages. 3 The biological activities of flavonoids depend on the degree of condensation in their structures and the position and number of substitutions, such as hydroxy groups, glu- cosides, isoprenyl units, homodimers, and heterodimers. 4 Flava- nones compared to flavones, 2-phenyl-4H-chromen-4-one, have more molecular flexibility due to the absence of a carbon–carbon double bond in the C-ring. In our previous studies, we found that a methoxy or hydroxy substituent at C-7 position of flavanone re- sulted in better inhibitory effects on HCT116 human colon cancer cell lines. 5 Based on this result, we tried to design flavanone deriv- atives with bulkier substituents at C-7 position and elucidate their inhibitory effects. Since the anti-cancer activity of naringenin, 4 0 ,5,7-trihydroxyf- lavanone against colon cancer cells has been reported, several fla- vanone derivatives were designed from naringenin. 6 Besides, naringenin plays a key role as an estrogenic substance in humans and as an endogenous regulator in plants. 7 Various flavonoid deriv- atives modified at C-7 position have been reported, but in flava- none, especially naringenin, derivatives modified at position 7 have rarely been studied. 8,9 Naringenin derivatives designed in this study have a common moiety, so that they may result in small changes in their biological activities. Therefore, one of long-term survival assays, clonogenic assay, was applied here. 10 As a control, naringenin was used. Naringenin contains three hydroxy groups (Fig. 1). O-substitu- tions can be easily at carried out at the 4 0 - and 7-hydroxy groups, however, the 5-hydroxy group forms a hydrogen bond (H-bond) with the ketone at C-4, making it less accessible. The treatment of cancer cell lines such as breast cancer cell line Michigan Cancer Foundation 7 (MCF7) with flavanone derivatives shows different effects according to the variation in functional groups on C-4 0 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.10.130 ⇑ Corresponding author. E-mail address: yoongho@konkuk.ac.kr (Y. Lim). Bioorganic & Medicinal Chemistry Letters 23 (2013) 232–238 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl