title: Synthesis of β-Carboline-Based N-Heterocyclic Carbenes and Their Antiproliferative and Antimetastatic Activities against Human Breast Cancer Cells.
abstract: A series of novel β-carboline-based N-heterocyclic carbenes was prepared via Mannich reaction between methyl 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate, formaldehyde, and primary amines. All compounds were evaluated for their antiproliferative activity using human breast cancer and lung cancer cell lines. Three compounds, 3c, 3j, and 3h, were discovered to display IC50 less than 10 μM against human breast cancer MDA-MB-231 cells at 24 h of treatment. Pharmacologically these compounds lead to G2/M phase cell cycle arrest and induction of cellular apoptosis by triggering intrinsic apoptotic pathway through depolarization of mitochondrial membrane potential and activation of caspases. At lower concentrations, these compounds also showed antimigratory and antiinvasive effects against highly metastatic human breast cancer MDA-MB-231 cells via aberration of MAP-kinase signaling and by the inhibition of matrix metalloproteinases. However, these analogues lack in vivo effect in mouse model which may be attributed to their strong affinity to HSA that was investigated spectroscopically with compound 3h.
authors.forename: Shashikant U
authors.initials: SU
authors.lastname: Dighe
authors.forename: Sajid
authors.initials: S
authors.lastname: Khan
authors.forename: Isha
authors.initials: I
authors.lastname: Soni
authors.forename: Preeti
authors.initials: P
authors.lastname: Jain
authors.forename: Samriddhi
authors.initials: S
authors.lastname: Shukla
authors.affiliation: §Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Yadav
authors.affiliation: §Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India.
authors.forename: Pratik
authors.initials: P
authors.lastname: Sen
authors.affiliation: ∥Academy of Scientific and Innovative Research, New Delhi 110025, India.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Meeran
authors.affiliation: ∥Academy of Scientific and Innovative Research, New Delhi 110025, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Batra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; C030011:carbene; D020169:Caspases; D008697:Methane