Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents

Abstract

Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization.

Interaction of Amino Acid Schiff Base Metal Complexes with DNA/BSA Protein and Antibacterial Activity: Spectral Studies, DFT Calculations and Molecular Docking Simulations

“…The ligands containing indole moiety have shown potent and selective antitumor activity against various cells lines . In addition, metal complexes of such ligands have shown potential antimicrobial activity . Metal complexes with well‐defined coordination geometries and distinctive electrochemical properties can act as DNA binding agents .…”

Current research on anti-breast cancer synthetic compounds

“…In addition, the marked pharmacological activity of compound 73 might be ascribed to activation of procaspase-3 and cell cycle arrest. 81 A series of novel indolylquinones have been synthesized and evaluated for their antiproliferative activity against human MDA-MB-231 and MCF-7 BC cell lines. Among all these derivatives, 74 (IC 50 value ¼ 2.29 mg mL À1 for MCF-7 cells) and 75 (IC 50 value ¼ 3.99 mg mL À1 for MDA-MB-231 cells) displayed the most potent antiproliferative activity of the series and inhibited BC cells proliferation by triggering apoptotic cell death ( Table 5).…”

Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

“…[15] PAC-1 and its derivatives induce apoptosis and are cytotoxic in cell culture to a diverse array of cancer cells, including cell lines derived from white blood cell cancers (lymphoma, [15, 42–51] leukemia, [15, 24, 44, 48–50, 52–55] and multiple myeloma [24, 55]), diverse carcinomas (breast, [15, 44, 48, 49, 52–54, 56–59] renal, [15] adrenal, [15, 60–62] colon, [15, 48, 55, 57–59, 63] lung, [15, 48, 49, 52–59, 63–67] cervical, [44, 55] gastric, [48, 49, 55, 57, 58, 63] ovarian, [55] liver, [48, 49, 55] prostate, [48, 49] and gallbladder [48, 49]), and other solid tumor types (melanoma, [15, 44, 48, 49] osteosarcoma, [55] neuroblastoma, [15, 55, 57, 58] and glioblastoma [48, 49, 68]). Patient-derived samples from colon cancer [15], chronic lymphocytic leukemia [23], and multiple myeloma [24] are also sensitive to PAC-1 and derivatives, and a therapeutic effect has been demonstrated in multiple murine tumor models [15, 48, 49, 56, 65, 66, 69] and in pet dogs with cancer.…”

“…This depletion of the labile zinc pool restores procaspase-3 enzymatic activity, allowing for cleavage of procaspase-3 to caspase-3 and the initiation of the execution pathway of apoptosis. [42] PAC-1 is now widely used as a tool compound for the induction of apoptosis [51, 59, 67, 68, 82, 83], and for the direct activation of procaspase-3 downstream of the mitochondria. [84–87] In addition, multiple independent studies have confirmed the direct procaspase-3 activation mechanism, [48, 85, 88] for example in detailed studies with selective caspase inhibitors, [85] selective caspase substrates, [48] and in Bax/Bak double knockout cells.…”