Med Chem Res (2017) 26:779–786 DOI 10.1007/s00044-017-1793-1 MEDICINAL CHEMISTR Y RESEARCH ORIGINAL RESEARCH Synthesis and anticancer activity evaluation of new isoindole analogues Aytekin Köse 1 ● Yıldız Bal 2 ● Nurhan H. Kishalı 1 ● Gülşah Şanlı-Mohamed 2 ● Yunus Kara 1 Received: 10 June 2016 / Accepted: 18 January 2017 / Published online: 25 January 2017 © Springer Science+Business Media New York 2017 Abstract We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton com- pounds. An exo-cycloadduct prepared from the Diels–Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac 2 O in the presence of a catalytic amount of H 2 SO 4 in order to yield new isoindole derivatives (8a and 8b). The anticancer activity of these compounds was evaluated against MCF-7 (breast adenocarcinoma) and A549 (adenocarcinomic human alveolar basal epithelial) cell lines. The synthesized compounds showed concentration- and time-dependent inhibitory effects on the viability of both cell lines. Com- pound 8a was more toxic compared to 8b in both cancer cell lines, having higher cytotoxicity against A549 cells. Testing the toxicity properties of these compounds on the BEAS 2B (human bronchial epithelial) cell line indicated that while both compounds decreased the cell viability of cancer cells, they were less toxic on healthy lung cells. Microscopy images of A549 cells after treatment with the new isoindole derivatives displayed characteristic apoptotic morphology compared to BEAS 2B cells. The results demonstrated here suggest that these new compounds might be considered as possible potential anticancer agents for the treatment of lung and breast cancer. Keywords Isoindole ● Norcantharimide ● Ether cleavage ● Anticancer ● Cytotoxicity ● Cancer cell lines Introduction Norcantharidin (2) and norcantharimide (3), which are derivatives of cantharidin (1), have attracted considerable attention due to their potential anticancer effects (Fig. 1). Cantharidin (1), a natural compound has been known to be an anticancer agent since 13th century. (Nicholls and Teare 1954; Wang 1989; Lin et al. 1998). Because of its sub- stantial toxicity (Tagwireyi et al. 2000), it is not used in chemotherapeutical studies. Norcantharidin and nor- cantharimide have lower toxicity and are known as antic- ancer agents (Hill et al. 2007). Cantharidin and its analogs have been found to have inhibitory effects against protein phosphatase 1 and 2A (PP1 and PP2A) (Li and Casida 1992; Li et al. 1993; Honkanen 1993; Sodeoka et al. 1997). The anticancer activity of cantharidin (1) and norcantharidin (2) is thought to come from the inhibition of protein phosphatase 1 and 2A (Fig. 1). Recently, scientists have revealed the connection between its protein phosphatase inhibitor and anticancer activity (McCluskey et al. 2000, 2001, 2003; Sakoff et al. 2002; Hart et al. 2004). In recent years, much effort has been devoted to the synthesis of N-derivatives of norcantharimide (Robertson et al. 2011). Some of the synthesized norcantharimide * Gülşah Şanlı-Mohamed gulsahsanli@iyte.edu.tr * Yunus Kara yukara@atauni.edu.tr 1 Faculty of Science, Department of Chemistry, Atatürk University, Erzurum, Turkey 2 Faculty of Science, Department of Chemistry, İzmir Institute of Technology, 35430 İzmir, Turkey Electronic supplementary material The online version of this article (doi:10.1007/s00044-017-1793-1) contains supplementary material, which is available to authorized users.