Synthesis and antitumour activity of varitriol and its analogues Caletková,a Angelika Lásiková,a Marián Hajdúch,b Petr D.ubák,b and Tibor Graczaa* aDepartment of Organic Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia bLaboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palack. University and University Hospital in Olomouc, Pu.kinova 6, 775 20 Olomouc, Czech Republic E-mail: --- Abstract Novel analogues of (+)-varitriol have been synthesised via Julia-Kocienski olefination from . -D- ribonolactone. Newly prepared compounds were screened for their in vitro cytotoxicity towards certain human tumours and NCI60 cancer cell line panel. Keywords: Cytotoxic natural product, natural product analogues, varitriol, cytotoxic activity, Julia-Kocienski olefination --- Introduction Marine fungi are an important source of marine natural products.1 Recently, the four new compounds, (+)-varitriol 1, varioxirane 2, dihydroterrein 3, and varixanthone 4 have been isolated2 from a marine-derived strain of the fungus Emericella variecolor (Figure 1). Amongst them, (+)-varitriol 1 demonstrated a more than 100-fold increased potency over the mean toxicity toward the RXF 393 (renal cancer, GI50 = 1.63 x 10-7 M), TD-47 (breast cancer, GI50 = 2.10 x 10- 7 M), and SNB (CNS cancer, GI50 = 2.44 x 10-7 M) cell lines and lower potency against the DU- 145 (prostate cancer, GI50 = 1.10 x 10-6 M), HL-60 (TB) (leukaemia, GI50 = 2.52 x 10-5 M), CCRF-CEM (leukaemia, GI50 = 2.60 x 10-5 M), OVCAR-5 (ovarian cancer, GI50 = 6.82 x 10-5 M), SNB-19 (CNS cancer, GI50 = 9.13 x 10-5 M), and COLO 205 (colon cancer, GI50 = 9.59 x 10-5 M) cell lines tested within the 60 cell lines panel of the National Cancer Institute (NCI).2,3 The combination of potent biological properties and a relatively straightforward molecular structure of (+)-1 generated considerable synthetic interest directed toward the varitriol and its analogues. Since 2006, when Jennings et al.4 established the absolute configuration of varitriol by the total synthesis of unnatural enantiomer (-)-1 from D-ribose, thirteen different syntheses of
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