title: Synthesis and study of benzothiazole conjugates in the control of cell proliferation by modulating Ras/MEK/ERK-dependent pathway in MCF-7 cells.
abstract: By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: Shaikh
authors.initials: S
authors.lastname: Faazil
authors.forename: M Janaki
authors.initials: MJ
authors.lastname: Ramaiah
authors.forename: Md
authors.initials: M
authors.lastname: Ashraf
authors.forename: M
authors.initials: M
authors.lastname: Balakrishna
authors.forename: S N C V L
authors.initials: SN
authors.lastname: Pushpavalli
authors.forename: Nibedita
authors.initials: N
authors.lastname: Patel
authors.forename: Manika
authors.initials: M
authors.lastname: Pal-Bhadra
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C588147:6-methoxy-2-(4-(2-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrrol-1-yl)phenyl)benzo(d)thiazole; D052160:Benzothiazoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D018631:ras Proteins; C005465:benzothiazole
keywords: Benzothiazole–pyrrole hybrid; Caspase-9; Cell cycle; Ras/MEK/ERK