Antiproliferation and apoptosis induced by C-glycosides in human leukemia cancer cells Carlos A. Sanhueza, a Carlos Mayato, a Marı ´a Garcı ´a-Chicano, b Raquel Dı ´az-Pen ˜ ate, b,c Rosa L. Dorta a and Jesu ´s T. Va ´zquez a, * a Instituto Universitario de Bio-Orga ´ nica ‘Antonio Gonza ´ lez’, Universidad de La Laguna, Avda, Astrofı ´sico Fco, Sa ´ nchez 2, 38206 La Laguna, Tenerife, Spain b Unidad de Investigacio ´ n del Hospital de Gran Canaria Dr. Negrı ´n, Bco. de la Ballena S/N, 35020 Las Palmas de Gran Canaria, Spain c Instituto Canario de Investigacio ´n del Ca ´ ncer (ICIC), Bco. de la Ballena S/N, 35020 Las Palmas de Gran Canaria, Spain Received 25 April 2006; revised 24 May 2006; accepted 24 May 2006 Available online 9 June 2006 Abstract—A large series of alkyl C-glycosides was synthesized from D-glucal or D-galactal. These compounds were screened against the human promyelocytic leukemia cell line (HL60), showing significant activity and apoptosis. Up to 13 C-glucopyranosides, but no C-galacto- or C-mannopyranosides, exhibited inhibitory concentrations (IC 50 values) below 20 lM, five of them in the range 4–8 lM. Preliminary structure–activity relationships were established. Ó 2006 Elsevier Ltd. All rights reserved. Cell surface glycoproteins are known to be active in numerous important disease states. 1 Their carbohydrate epitopes have been shown to play a central role in a vari- ety of significant biological events, including inflamma- tion, metastasis, immune response, and bacterial and viral infection. This has recently stimulated the develop- ment of effective therapeutic strategies based upon recognition of these cell surface carbohydrates. One ap- proach lies in the replacement of the exocyclic oxygen with a carbon, to afford C-glycosidic analogs, due to their increased resistance to degradation by glycosi- dases. This has led to a wealth of synthetic approaches 2 and consequently biological data on C-glycosides have started to emerge. 3 In addition, comparative biological studies have re- vealed that C-glycosides retain the biological properties of natural O-glycosides. 4 Since glycosylarenes 5 (or C-aryl glycosides), 4-keto unsaturated C-glycosides, 6 C-glycoglycerolipids, 7 and unsaturated C-glycosides with an attached ring system bonded at C-4 and C-6 exhibit diverse biological activi- ties, 8 including antitumor and antiviral action, the aim of the present study was to carry out the synthesis of easily obtained simple C-glycosides and check their cytotoxic activities. Among the different methods for the preparation of C- glycosides, 2 the addition of carbon nucleophiles to acti- vated glycal epoxides has been widely used. 9 Therefore, the C-glycoside derivatives under study were prepared in three steps: (i) O-alkylation of D-glucal or D-galactal; (ii) epoxidation using dimethyldioxirane in CH 2 Cl 2 , accord- ing to Danishefsky’s protocol; 10 and (iii) epoxide opening with Grignard reagents or diorganocuprates (Scheme 1). 11 Thus, addition of numerous Grignard reagents or diorg- anocuprates to the 1,2-anhydrosugar led to a mixture of a- and b-C-glycoside derivatives, the a/b ratio being var- iable and in most cases favoring the b-isomer. In some cases, further simple structural modifications were 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.05.079 Keywords: C-Glycosides; Leukemia (HL60); Apoptosis; Cancer. * Corresponding author. Tel.: +34 922318581; fax: +34 922318571; e-mail: jtruvaz@ull.es O OR RO RO O R' OR OH RO RO O R' OR OH RO RO β α + 1. DMDO 2. R'MgX or R' 2 CuMgX 1 1 Scheme 1. Synthesis of C-gluco- and C-galactopyranosides. Bioorganic & Medicinal Chemistry Letters 16 (2006) 4223–4227