New rosmaricine derivates as anticancer agents

Rosmaricine (Fig.1) is a diterpenoid aminocompound obtained from dried leaves of Rosmarinus officinalis L. treated with ammonia in the presence of air. It is an alkaloidal artifact formed through a complex reaction between some oxidation derivatives of carnosic acid and the ammonia used to liberate the bases supposed to be present in the ethanolic extract.1,2 Rosmaricine is structurally similar to the natural diterpenes carnosol and rosmanol, both endowed with antioxidant, radical scavenger and antiproliferative activities through a mechanism that involve, among others, NF-kB and STAT-3 inhibition.3 In view of the growing interest on terpenoid compounds as potential antitumoral drugs and following our recent studies on sulphurated drug-hybrids as multitarget anticancer agents,4,5 we synthesized three new derivatives through the condensation of the amino group of rosmaricine with some sulfurated carboxylic acids, containing a thiosulfonate or allyldisulfide or a dithiolethione moiety (Fig. 1) and investigated their ability to inhibit STAT-3 and NF-kB transcription factors as well as their antiproliferative activity on a human cancer cell line. Results showed that rosmaricin and its derivatives inhibited HCT-116 cell proliferation in vitro with IC50 in micromolar range. In addition, they were able to strongly and selectively bind STAT-3 SH2 domain in an Alpha Screen assay and were also able to inhibit the NF-kB transcriptional activity in HCT-116 cell line. The obtained data underline the interesting profile of these compounds which are worthy of further investigation as potential multitarget anticancer agents. References 1. E. Wenkert, A. Fuchs, J.D. McChesney J.Org. Chem. 1965, 30, 2931-2934. 2. A. Boido, F. Savelli, F. Sparatore Il Farmaco 1994, 49, 111-114. 3. C. Lai, J. H. Lee, C. Ho, C. B. Liu, J. Wang, J. Wang, M. Pan J. Agric. Food Chem. 2009, 57, 10990-10998. 4. Gabriele E.; Barteselli A.; Moiana V.; Porta F.; Gelain A.; Asai A.; Sparatore A. Methanethiosulfonate derivatives as ligands of STAT3-SH2 domain. “Tefarco NFPC8” (Parma, Italy, 9-11 June 2014); Poster communication P-18. 5. Gabriele E.; Brambilla D.; Ferri N.; Asai A.; Sparatore A. New sulfurated cinnamic acid derivative as multitarget anticancer agents. Book of Abstract – SIMCC2015 - Spanish-Italian Medicinal Chemistry Congress (Barcellona, Spain - July 12-15, 2015) - P-90.