title: Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition.
abstract: In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3-yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia.
authors.affiliation: Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore, Karnataka 575025, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Panathur
authors.forename: Udayakumar
authors.initials: U
authors.lastname: Dalimba
authors.forename: Pulla Venkat
authors.initials: PV
authors.lastname: Koushik
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Vijith
authors.initials: V
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced / Q000188:drug therapy*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013739:Testosterone
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D054852:Small Molecule Libraries; D013739:Testosterone; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Breast cancer; Human SIRT1; Indole; Leukemia; Prostate hyperplasia