C1,C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: Retention of activity of highly lipophilic analogues against cancer cells Ramesh Dasari a , Laetitia Moreno Y. Banuls b , Marco Masi c , Stephen C. Pelly d , Véronique Mathieu b , Ivan R. Green d , Willem A. L. van Otterlo d , Antonio Evidente c , Robert Kiss b , Alexander Kornienko a,⇑ a Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA b Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium c Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant’Angelo, Via Cintia 4, 80126 Napoli, Italy d Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa article info Article history: Received 31 October 2013 Revised 16 December 2013 Accepted 17 December 2013 Available online 24 December 2013 Keywords: Cancer Apoptosis resistance Melanoma Glioblastoma Alkaloid abstract As a continuation of the studies aimed at the development of new anticancer agents derived from the Amaryllidaceae alkaloid lycorine, 35 C1,C2-ether analogues of this natural product were synthesized. The compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines with varied levels of apoptosis resistance. A strong correlation between the compound lipophilicity and anti- cancer activity was observed, indicating that cell permeability properties must be an important determi- nant in the design of lycorine-based anticancer agents. A theoretical docking model, consistent with the experimental observations, is presented. Ó 2013 Elsevier Ltd. All rights reserved. The use of the Amaryllidaceae plants in folk medicine dates back to at least the fourth century BC, when Hippocrates of Cos used oil from the daffodil Narcissus poeticus L. for the treatment of cancer. 1 In more recent times, hundreds of structurally diverse alkaloids, possessing a wide spectrum of biological activities have been iso- lated from the Amaryllidaceae species. 2–6 Lycorine (1, Fig. 1) was the first member of this family isolated in 1877, 4,7 whose structure was elucidated in 1956. 7 This natural product is also the most abundant Amaryllidaceae alkaloid and a prototypical member of the lycorine group of Amaryllidaceae constituents containing over 70 related natural phenanthridines. 3 Selected examples are shown in Figure 1. Lycorine has been actively investigated, both in vitro and in vivo, in various preclinical models of human cancers. Thus, the results of lycorine evaluation in cancer cell lines 8–16 show that lyc- orine is in general a low micromolar antiproliferative agent, which maintains activity against multidrug resistant cells 13,16 and is also capable of sensitizing cancer cells to pro-apoptotic agents. 15 In addition, lycorine’s therapeutic potential has been demonstrated in a number of mouse models of human cancer, including HL-60 leukemia, 9 LLC lung carcinoma, 12 and Hey1B ovarian cancer. 14 The investigations of lycorine and its natural congeners as potential anticancer agents are expected to intensify after a recent discovery made in the authors’ laboratories involving the demon- stration of lycorine’s promising activity against apoptosis-resistant cancers. In this work it was demonstrated that at therapeutic con- centrations, lycorine does not induce apoptosis in cancer cells, but rather exhibits cytostatic effects through impairing the actin cyto- skeleton organization. 17 This mode of action accounts for lycorine- induced inhibition of both cell proliferation and cell migration in a large panel of apoptosis-resistant cancer cell lines, including gli- oma and melanoma. Lycorine also displayed a high potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells and was shown to induce no CYP3A4 inhibitory activity. 18 Furthermore, lycorine provided sig- nificant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at non-toxic doses. 17 In addition, the ini- tial results show that the activity against apoptosis-resistant can- cers is also shared by lycorine natural congeners (e.g., alkaloids in Fig. 1), 17,19,20 as well as a number of synthetic analogues. 21 The authors have also provided considerable evidence support- ing the eukaryotic translation elongation factor 1A (eEF1A) as a likely intracellular target for the structurally related Amaryllidaceae isocarbostyrils, identifying this protein as a potential target for lyc- orine as well. 22 These results make lycorine an excellent lead for 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.12.073 ⇑ Corresponding author. E-mail address: a_k76@txstate.edu (A. Kornienko). Bioorganic & Medicinal Chemistry Letters 24 (2014) 923–927 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl