Original article Chiral 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles with anti-breast cancer properties Maria I.L. Soares a , Ana Filipa Brito b, c , Mafalda Laranjo b, c , José A. Paixão d , M.Filomena Botelho b, c , Teresa M.V.D. Pinho e Melo a, * a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal b Biophysics/Biomathematics Institute, IBILI e Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal c Center of Investigation on Environmental, Genetics and Oncobiology e CIMAGO, Faculty of Medicine, Coimbra, Portugal d Department of Physics, University of Coimbra, 3004-516 Coimbra, Portugal article info Article history: Received 16 October 2012 Received in revised form 20 November 2012 Accepted 23 November 2012 Available online 30 November 2012 Keywords: 1H,3H-Pyrrolo[1,2-c]thiazoles Anticancer activity Breast adenocarcinoma abstract The synthesis and biological evaluation of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against MCF7 breast cancer cell lines is reported. The design of the new compounds has been guided considering (3R)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c] thiazole as the lead compound due to its good performance against MCF7 breast cancer cell lines (IC 50 ¼ 1.0 mM). The structural changes included the removal of the phenyl group at C-3, the replacement of this group by a 3,4,5-trimethoxyphenyl group, the removal of the methyl group at C-5 from the lead scaffold and the replacement of this group by a phenyl substituent. Overall, these studies showed that the combined presence of a phenyl group at C-3 and a methyl group at C-5 in the 1H,3H-pyrrolo[1,2-c] thiazole ring system is essential to ensure high cytotoxicty against MCF7 breast cancer cell lines. To probe whether the absolute configuration of the lead compound might affect the anticancer activity, its enantiomer was prepared and the activity against MCF7 cells was evaluated. (3S)-6,7- Bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole proved to be the most active compound so far studied, with IC 50 value of 0.5 mM. Ó 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction The major challenge in cancer chemotherapy is the selective inactivation of DNA in cancer cells. In fact, targeting the DNA of tumor cells with small molecules has been one of the most effective clinical strategies since the development of the nitrogen mustard, mechlorethamine. However, the first DNA interacting agents showed significant toxicity, which led to the search for new compounds that are less toxic and capable of targeting tumor DNA more specifically. Of particular interest are the minor groove binders, a group of DNA interactive agents which bind to specific regions of the genome and show significant in vitro and in vivo toxicity towards cancer cells [1e4]. Alkylating agents are minor groove binding agents that induce permanent DNA damage and often exhibit potent antitumor activity. A range of alkylating agents is known including mono- alkylating (reacting with only one DNA strand) and bifunctional alkylating drugs. The latter were found to crosslink the two complementary strands of DNA, which is expected to inhibit DNA replication and subsequently cell proliferation and usually results in more potent and efficacious agents. Mitomycin C (1) is a naturally occurring antitumor alkylating agent which finds use in clinical practice as a useful chemothera- peutic agent. The mitomycin C metabolite 2 is the active specie having two electrophilic centers (C-1 and C-10) which enables DNA interstrand cross-linking reactions. On the other hand, several pyr- rolizine alkaloids (e.g. 3), one of the most abundant class of biolog- ically active natural products, also undergo metabolic activation to give dehydropyrrolizines bearing two reactive functionalities (e.g. 4, C-7 and C-9) which allow DNA cross-linking. The structural simi- larities between the activated pyrrolizine alkaloids and mitomycin C, both having a pyrrole-containing substructure, and the demonstra- tion that they target preferentially the same sequences of the DNA led to the search of new pyrrole-derived bifunctional alkylating agents. In fact, Hopkins et al. have shown that bis(hydroxymethyl) pyrroles 5 and 6 and the antitumor 1H-pyrrolizine 7 also show selectivity for the same site of DNA interstrand cross-linking. Studies on the mechanism of action of bifunctional electrophilic pyrroles * Corresponding author. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2012.11.036 European Journal of Medicinal Chemistry 60 (2013) 254e262