H2O-mediated isatin spiro-epoxide ring opening with NaCN: Synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation

• Published in: European journal of medicinal chemistry Vol. 104; pp. 11 - 24
• Main Authors: Sharma, Pankaj, Senwar, Kishna Ram, Jeengar, Manish Kumar, Reddy, T. Srinivasa, Naidu, V.G.M., Kamal, Ahmed, Shankaraiah, Nagula
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 02.11.2015; Elsevier
• Subjects: 3-Hydroxy-oxindole; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Azide-nitrile cycloaddition; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epoxy Compounds - chemistry; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Isatin - chemistry; Isatin epoxide; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Reactive Oxygen Species - metabolism; Science & Technology; Sodium Cyanide - chemistry; Spiro Compounds - chemistry; Structure-Activity Relationship; Tetrazoles; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacology; Water - chemistry; Isatin epoxide; Tetrazoles; Azide-nitrile cycloaddition; 3-Hydroxy-oxindole; Anticancer; Apoptosis; 5-SUBSTITUTED 1H-TETRAZOLES; HIGHLY ENANTIOSELECTIVE SYNTHESIS; DNA-BINDING AFFINITY; POTENTIAL ANTICANCER; UNACTIVATED KETONES; ASYMMETRIC ALDOL REACTION; BIOLOGICAL EVALUATION; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.09.025

A simple method for isatin spiro-epoxide ring-opening by sodium cyanide in water to obtain a variety of isatin hydroxy nitriles has been developed. Further, these intermediates have been converted into new 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids via azide-nitrile cycloaddition reaction in a sealed tube. These compounds were evaluated for their in vitro anticancer activity on five human cancer cell lines i.e. breast (BT549 and MDA MB-231), prostate (PC-3 and DU-145) and ovarian (PA-1). The compounds 6d and 6r showed potent anticancer activity against DU-145 cell line with IC50 values in the range of 7.01 ± 0.91 and 4.26 ± 0.09 μM respectively. The compounds 6d, 6g, 6q and 6r were also tested on human normal prostate epithelial (RWPE-1) cells and found to be safer with lesser cytotoxicity. The morphology and long term clonogenic survival of DU-145 cells were severely affected by compound 6r. Cell cycle analysis revealed that the compounds arrest the cells in G2/M phase. Acridine orange/ethidium bromide (AO/EB) staining, DAPI staining, annexin-V binding assay and DNA fragmentation analysis showed that cell proliferation was inhibited through induction of apoptosis. Moreover, one of the compounds 6r treatment led to collapse of the mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS) in DU-145 cells. [Display omitted] •Regiospecific isatin spiro-epoxide ring-opening with sodium cyanide in water.•Conversion of hydroxy nitriles into their tetrazoles in a sealed tube.•Anticancer evaluation of the compounds on selected human cancer cell lines.•Selectivity towards cancer cells compared to normal prostate epithelial cells.•Induction of apoptosis and cell cycle arrest in G2/M phase by compound 6r.