Investigation of triazole-linked indole and oxindole glycoconjugates as potential anticancer agents: novel Akt/PKB signaling pathway inhibitors

Abstract

In continuation of our venture towards the synthesis of novel bioactive agents, two sets of triazole-linked glycoconjugates were synthesized from indole/oxindole (29 compounds) and were further characterized by IR (infrared spectroscopy), ¹H NMR (nuclear magnetic resonance), ¹³C NMR and mass spectral analysis. The newly synthesized target compounds were evaluated for their preliminary in vitro anticancer activity against DU145 (prostate cancer), HeLa (cervical cancer), A549 (lung cancer) and MCF-7 (breast cancer) cell lines. In the sulforhodamine B (SRB) assay, the results indicated that compounds 5f (indole derivative) and E-9b (oxindole derivative) displayed remarkable cytotoxic activity against DU145 cells. Moreover, the colony formation assay (soft agar assay) revealed that compounds 5f and E-9b can inhibit the growth and proliferation of DU145 cells. The impact of the most active cytotoxic compounds 5f and E-9b on the cell cycle distribution was assessed in DU145 cells, which displayed a cell cycle arrest at the sub-G1 phase. Next, compounds 5f and E-9b were tested for caspase activation in DU145 cells, and the results specified that these compounds have the capability to induce apoptosis in cells through an intrinsic pathway leading to subsequent cell death. Further studies also confirmed that compounds 5f and E-9b act against the protein kinase B (Akt/PKB) pathway to inhibit the proliferation of cancer cells. Thus, compounds 5f and E-9b could be novel potential anticancer leads as the normal cell line NIH/3T3 (fibroblast) studies showed no significant cytotoxicity.