Contents lists available at ScienceDirect Steroids journal homepage: www.elsevier.com/locate/steroids Cycloartane-type sapogenol derivatives inhibit NFκB activation as chemopreventive strategy for inflammation-induced prostate carcinogenesis Bilge Debeleç-Bütüner a, ⁎ , Mert Burak Öztürk b,1 , Özgür Tağ c , İsmail Hakkı Akgün d , Günay Yetik-Anacak e , Erdal Bedir d,2, ⁎ , Kemal Sami Korkmaz b a Ege University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Izmir, Turkey b Ege University, Faculty of Engineering, Department of Bioengineering, Cancer Biology Laboratory, Izmir, Turkey c Ege University, Graduate School of Natural and Applied Sciences, Department of Chemistry, Izmir, Turkey d Ege University, Faculty of Engineering, Department of Bioengineering, Izmir, Turkey e Ege University, Faculty of Pharmacy, Department of Pharmacology, Izmir, Turkey ARTICLE INFO Keywords: Astragenol Cycloastragenol Semi-synthesis Prostate cancer chemoprevention Inflammation-induced carcinogenesis NFκB ABSTRACT Chronic inflammation is associated to 25% of cancer cases according to epidemiological data. Therefore, in- hibition of inflammation-induced carcinogenesis can be an efficient therapeutic approach for cancer chemo- prevention in drug development studies. It is also determined that anti-inflammatory drugs reduce cancer in- cidence. Cell culture-based in vitro screening methods are used as a fast and efficient method to investigate the biological activities of the biomolecules. In addition, saponins are molecules that are isolated from natural sources and are known to have potential for tumor inhibition. Studies on the preparation of analogues of cy- cloartane-type sapogenols (9,19-cyclolanostanes) have so far been limited. Therefore we have decided to direct our efforts toward the exploration of new anti-tumor agents prepared from cycloastragenol and its production artifact astragenol. The semi-synthetic derivatives were prepared mainly by oxidation, condensation, alkylation, acylation, and elimination reactions. After preliminary studies, five sapogenol analogues, two of which were new compounds (2 and 3), were selected and screened for their inhibitory activity on cell viability and NFκB sig- naling pathway activity in LNCaP prostate cancer cells. We found that the astragenol derivatives 1 and 2 as well as cycloastragenol derivatives 3, 4, and 5 exhibited strong inhibitory activity on NFκB signaling leading the repression of NFκB transcriptional activation and suppressed cell proliferation. The results suggested that these molecules might have significant potential for chemoprevention of prostate carcinogenesis induced by in- flammatory NFκB signaling pathway. 1. Introduction Experimental and clinical studies demonstrate that anti-in- flammatory drugs reduce the incidence of various types of cancer, in particular prostate, colon, and stomach [1]. In prostate cancer, regular use of aspirin and NSAIDs was determined to decrease the cancer risk about 15–20% in prospective and case control studies [2]. Most anti- inflammatory agents show their anticancer effect through cellular me- chanisms via inhibition of NFκB, COX2, and prostaglandin synthesis [2–6]. Chronic inflammation alters the cellular levels of reactive oxygen and nitrogen species (RONS), inflammatory cytokines, and other in- flammatory mediators such as cyclooxygenase-2 (COX2), and also ac- tivates proto-oncogenes in the meanwhile. However, cellular response to inflammatory mechanisms can be pro- or anti-tumorigenic de- pending on the balance between inflammatory mediators in a cell [2]. One of the most important mediators of inflammation is NFκB, which is a transcription factor and the key molecule of pro-in- flammatory signaling leading tumorigenesis. While some of NFκB transcriptional targets activate the cell cycle, angiogenesis, and me- tastasis, a group of targets inhibit apoptotic genes. Furthermore, many gene products of NFκB targets can be counted as mediators of innate https://doi.org/10.1016/j.steroids.2018.04.005 Received 13 September 2017; Received in revised form 2 April 2018; Accepted 12 April 2018 ⁎ Corresponding authors at: Ege University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Izmir, Turkey (B. Debeleç-Bütüner); Ege University, Faculty of Engineering, Department of Bioengineering, Izmir, Turkey (E. Bedir). 1 Present address: Division of Cancer Genetics and Therapeutics, Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore. 2 Present address: Izmir Institute of Technology, Faculty of Engineering, Department of Bioengineering, Izmir, Turkey. E-mail addresses: bilge.debelec@ege.edu.tr (B. Debeleç-Bütüner), erdalbedir@iyte.edu.tr (E. Bedir). Steroids 135 (2018) 9–20 Available online 18 April 2018 0039-128X/ © 2018 Elsevier Inc. All rights reserved. T