Planta Med 2010; 76 - P094
DOI: 10.1055/s-0030-1264392

Structure-based design of new analogs of Withaferin A as antitumor agents

C Jimenez 1, G LLanos 2, L Araujo 3, L Moujir 3, J Rodriguez 1, I Jiménez 2, I Bazzocchi 2
  • 1Universidade da Coruña, Departamento de Química Fundamental, Facultade de Ciencias Universidade da Coruña Campus da Zapateira s/n 15071 A Coruña, Spain, 15071 A Coruña, Spain
  • 2Universidad de La Laguna, Instituto Universitario Bio-Orgánica Antonio González, Av. Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain
  • 3Universidad de La Laguna, Departamento de Microbiología y Biología Celular, Avenida Astrofísico Francisco Sánchez s/n, 38206 La Laguna, Tenerife, Spain

The endemic plant from Canary Islands (Spain), Withania aristata (Aiton) Pauqui (Solanaceae), popularly known as „orobal“ [1] is widely used in folk medicine as antitumor, antispasmodic, antirheumatic agent; further for eye and otitis problems, as well as for insomnia and urinary pathologies [2]. We have found that the acetone extract from the leaves of this species is a rich source of the known whitanolide, withaferin A (more than 0.2% dried weight). The therapeutic potential of Withania species has been attributed to the presence of withanolides [3] and, in particular, withaferin A which showed anti-cancer activity in vivo and has been reported to induce cytoskeletal disruption, to inhibit cell mobility and NFkB activation [4], and to induce apoptosis in vitro [5]. Taking this into account, we have prepared analogs of withaferin A for structure-activity relationship studies. We have performed several chemical transformations on ring A, on the epoxy group of ring B, and on the lactone and hydroxyl groups of the side chain of withaferin A, including oxidations, reductions and halogenations. All semi-synthetic analogs were tested for their potential anticancer activity against four tumor cell lines. The biological results obtained from these analogs allowed us to deduce a number of structure-activity relationships, which confirmed the potential of withaferin A in cancer chemotherapy. The semi-synthesis, the bioactivity data and the SAR studies will be presented in the accompanying poster.

References: 1. Anderson GJ et al (2006) Am. J. Bot. 93:1295–1305.

2. Benjumea D et al (2009)J Ethnopharmacol 123: 351–355.

3. Veleiro AS et al (2005) Studies in Natural Products Chemistry, Bioactive Natural Products Atta-Ur-Raman, Elsevier Science Publishers, Amsterdam, p 1019–52.

4. Ichikawa H. (2006) Mol. Cancer Ther. 5: 1434.

5. Malik F et al (2007) Apoptosis 12: 2115–2133.