4-Amino-2-arylamino-5-indoloyl/cinnamoythiazoles, analogs of topsentin-class of marine alkaloids, induce apoptosis in HeLa cells

Marine organisms provide several biologically active compounds that include alkaloids with high cytotoxic activity but only a few of them have so far reached clinical stage, due partly to their limited supply and complex structural features. In an attempt to develop novel anticancer compounds, we have now synthesized diaminoindoloylthiazoles (4a–c; DIT1–3) and diaminocinnamoylthiazoles (5a,b; DCT1–2) as analogs based on a topsentin scaffold and investigated the cytotoxic and apoptotic activities of these compounds in HeLa cells. The results suggest that diaminoindoloylthiazoles (DIT1–3) inhibit cell growth and among these, DIT3 is the most cytotoxic against HeLa cells (IC50 1 μM). The diaminocinnamoylthiazoles DCT1 and DCT2, which can be viewed as curcumin–diaminothiazole hybrids, also inhibited cell growth but at relatively higher concentrations with IC50 values of 60 and 30 μM, respectively. These compounds induced apoptosis through the intrinsic pathway by reducing the mitochondrial membrane potential and activating caspases, 9 and 3, but not caspase 8. Among the marine alkaloid analogs tested in this study, DIT1–3 are very effective in inducing apoptosis of HeLa cells followed by DCT2 and DCT1. The treated cells were arrested in G2/M phase followed by accumulation of the cells in the Sub G0 phase. The curcumin–diaminothiazole hybrid DCT1 had the maximum effect in downregulating TNF-induced NF-κB activation among the compounds tested in this study. Thus, we demonstrate that diaminoindoloylthiazoles and diaminocinnamoylthiazoles induce apoptosis, regulate cell cycle and NF-κB signaling and thus show promising anticancer effects that warrant further investigation.

Analogs of the marine alkaloid topsentin, 2,4-diamino-5-(indol-3-oyl)thiazoles (DIT1–3; 4a–c) and the curcumin marine-alkaloid hybrids, 4-amino-2-arylamino-5-cinnamoylthiazoles (DCT1–2; 5a–b), induce apoptosis, regulate cell cycle and NF-κB signaling in HeLa cells.Figure optionsDownload as PowerPoint slideHighlights
► This paper describes the apoptotic activity of marine bisindole alkaloid analogs.
► Apoptosis in HeLa is preceded by G2/M arrest and occurs through intrinsic pathway.
► There was activation of caspase 9 and caspase 3, but not caspase 8.
► There was also a downregulation of transcription factor NF-kB induced by TNF-α.
► Thus a novel series of topsentin analogs show promising anticancer effects.