title: 2-Anilinonicotinyl linked 2-aminobenzothiazoles and [1,2,4]triazolo[1,5-b] [1,2,4]benzothiadiazine conjugates as potential mitochondrial apoptotic inducers.
abstract: A series of N-(2-anilino-pyridyl) linked 2-amino benzothiazoles (4a-n) and [1,2,4]triazolo [1,5-b]benzothiadiazine conjugates (5a-j) have been designed, synthesized and evaluated for their antiproliferative activity. Some of these compounds (4h-k, 4n, and 5e) have exhibited potent cytotoxicity specifically against human leukemia HL-60 cell lines with IC(50) values in the range of 0.08-0.70 μM. All these compounds were tested for their effects on the cell cycle perturbations and induction of apoptosis. Morphological evidences of apoptosis, including fragmentation of nuclei and inter nucleosomal DNA laddering formation were clearly observed after 24h exposure to compound 4i. Flow cytometry analysis revealed that compound 4i showed drastic cell cycle perturbations due to concentration dependant increase in the sub-G0 region which comprises of both the apoptotic and debris fraction, thus implying the extent of cell death. These compounds trigger the mitochondrial apoptotic pathway that results in the loss of mitochondrial membrane potential through activation of multiple caspases followed by activation of caspase-3, and finally cleavage of PARP. Further the mechanism of cell death was analysed by fluorescent microscopic analysis and also by scanning electron microscopy. The cytotoxicity of 4i correlated with induction of apoptosis, caspases activation and DNA damage and thus indicating the apoptotic pathway of anticancer effect of these compounds.
authors: Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India. ahmedkamal@iict.res.in
authors: Ahmed
authors: A
authors: Kamal
authors: Y V V
authors: YV
authors: Srikanth
authors: M
authors: M
authors: Naseer Ahmed Khan
authors: Md
authors: M
authors: Ashraf
authors: M
authors: M
authors: Kashi Reddy
authors: Farheen
authors: F
authors: Sultana
authors: Tandeep
authors: T
authors: Kaur
authors: Gousia
authors: G
authors: Chashoo
authors: Nitasha
authors: N
authors: Suri
authors: Irum
authors: I
authors: Sehar
authors: Zahoor A
authors: ZA
authors: Wani
authors: Arpita
authors: A
authors: Saxena
authors: Parduman R
authors: PR
authors: Sharma
authors: Shashi
authors: S
authors: Bhushan
authors: Dilip M
authors: DM
authors: Mondhe
authors: Ajit K
authors: AK
authors: Saxena
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006131:Growth Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D000882:Haplorhini; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D009538:Nicotine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D001581:Benzothiadiazines; D006131:Growth Inhibitors; D009538:Nicotine; D020169:Caspases