Available free online at www.medjchem.com Mediterranean Journal of Chemistry 2017, 6(4), 142-164 *Corresponding author: René Csuk Received June 5, 2017 Email address: rene.csuk@chemie.uni-halle.de Accepted June 22, 2017 DOI: http://dx.doi.org/10.13171/mjc64/01707151548-csuk Published July 15, 2017 Synthesis and cytotoxic screening of boswellic acid derivatives Ratna Kancana Wolfram 1 , Anja Barthel-Niesen 1 , Renate Schäfer 1 , Lucie Heller 1 , Ahmed Al-Harrasi 2 and René Csuk 1,* 1 Martin-Luther-University Halle-Wittenberg, Organic Chemistry Kurt-Mothes Str. 29, Halle (Saale) 06108, Germany 2 University of Nizwa, Chair of Oman’s Medicinal Plants and Marine Natural Products, P.O. Box 33, PC 616, Birkat Al-Mauz, Nizwa, Sultanate of Oman Abstract: Beta-boswellic acids are triterpenoids being generic to the plants of genus boswellia. Although they were shown to exhibit different biological activities, the cytotoxic potential of -boswellic acid derivatives remained by and large unexploited. To expand the potential of these compounds we developed simple procedures for the interconversion of the most important -boswellic acids 1-4 and prepared several other derivatives 5-48. These compounds were screened for their cytotoxic activity in sulforhodamine B assays employing several human tumor cell lines and nonmalignant mouse fibroblasts. One of these compounds, a difluoromethylester of 3-O- acetyl-11-keto--boswellic acid 23, was cytotoxic for human breast adenocarcinoma cells MCF-7 (EC50 = 6.5 M) while being significantly less cytotoxic for the mouse fibroblasts. Keywords: Frankincense, Boswellic acid, Cytostatic activity. Introduction During the last decade, the scientific interest in frankincense has risen considerably. A literature retrieval (SciFinder) searching for the index term „frankincense “showed 3905 hits (until May 2017): While during 1995-2004 only 76 articles dealt with this topic, the number of publications on frankincense increased during the period 2005-2011 to 1341 and grew even larger for the period 2012-2017 (May), and further 2409 papers have been noted for this time span. Despite the increased interest in frankincense, the number of articles dealing with boswellic acids remained low 1-3 , although boswellic acids account for 25-30% (by weight) of the resin acids, with ursane- derived -boswellic acids dominating over oleanane- derived -boswellic acids. Analyses of commercial samples reported for -boswellic acid (-derivatives) up to 10.1% of BA (1, -boswellic acid), 6.8% of ABA (2, 3-O-acetyl-- boswellic acid), 5.1% of -KBA (3, 11-keto-- boswellic acid) and 3.8% of AKBA (4, 3-O-acetyl- 11-keto--boswellic acid) in frankincense 4 . These values vary highly in practice, and they strongly depend on the quality of the resin, its origin, the time of harvesting and from the species of boswellia (Fig. 1) 5 . The only source for these natural products (that are also generic to the plants of genus boswellia) is their extraction from the resin; there are no total or partial syntheses for boswellic acids. Because of these limitations, the number of publications dealing with synthetic transformations 2, 6-8 of boswellic acids remained low compared to the number of publications on frankincense; even less is known about the cytotoxicity of BA and derivatives 6, 8-13 .