title: H2O-mediated isatin spiro-epoxide ring opening with NaCN: Synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Kishna Ram
authors.initials: KR
authors.lastname: Senwar
authors.affiliation: Pharmacology and Toxicology Division, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Jeengar
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: T Srinivasa
authors.initials: TS
authors.lastname: Reddy
authors.affiliation: Pharmacology and Toxicology Division, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: V G M
authors.initials: VG
authors.lastname: Naidu
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar.niperhyd@gov.in.
authors.forename: Nagula
authors.initials: N
authors.lastname: Shankaraiah
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007510:Isatin / Q000737:chemistry*; D015394:Molecular Structure; D000078183:Oxindoles; D017382:Reactive Oxygen Species / Q000378:metabolism; D012966:Sodium Cyanide / Q000737:chemistry*; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry*
chemical_list: C000609846:3-tetrazolylmethyl-3-hydroxy-oxindole; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D007211:Indoles; D000078183:Oxindoles; D017382:Reactive Oxygen Species; D013141:Spiro Compounds; D013777:Tetrazoles; D014867:Water; D007510:Isatin; D012966:Sodium Cyanide
keywords: 3-Hydroxy-oxindole; Anticancer; Apoptosis; Azide-nitrile cycloaddition; Isatin epoxide; Tetrazoles