Bisindole-oxadiazole hybrids, T3P® -mediated synthesis, and appraisal of their apoptotic, antimetastatic, and computational Bcl-2 binding potential.
Pooja R KamathManu M JosephAbdul Ajees Abdul SalamSreelekha T TherakathinalDhanya SunilSubhankar BiswasKarkala Sreedhara Ranganath PaiPublished in: Journal of biochemical and molecular toxicology (2017)
In the pursuit of novel anticancer leads, new bisindole-oxadiazoles were synthesized using propyl phosphonic anhydride as a mild and efficient reagent. The molecule, 3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indole (3a) exhibited selective cytotoxicity to MCF-7 cells with a cell cycle arrest in the G1 phase. The mechanism of cytotoxicity of 3a involved caspase-2-dependent apoptotic pathway with characteristic apoptotic morphological alterations as observed in acridine orange/ethidium bromide and Hoechst staining. The wound healing migratory assay exhibited an intense impairment in the motility of MCF-7 cells on incubation with 3a. Docking simulations with anti-apoptotic protein Bcl-2, which is also involved in cancer metastasis displayed good affinity and high binding energy of 3a into the well characterized BH3 binding site. The positive correlation between the Bcl-2 binding studies and the results of in vitro investigations exemplifies compound 3a as a lead molecule exhibiting MCF-7 differential cytotoxicity via apoptotic mode of cell death in addition to its anti-metastatic activity.
Keyphrases
- cell death
- cell cycle arrest
- breast cancer cells
- binding protein
- molecular dynamics
- small cell lung cancer
- dna binding
- squamous cell carcinoma
- protein protein
- escherichia coli
- molecular dynamics simulations
- induced apoptosis
- risk assessment
- staphylococcus aureus
- pseudomonas aeruginosa
- papillary thyroid
- high throughput
- pi k akt
- lymph node metastasis
- flow cytometry
- childhood cancer
- biofilm formation