Synthesis of β-carboline-based N-heterocyclic carbenes and their antiproliferative and antimetastatic activities against human breast cancer cells

Shashikant U. Dighe, Sajid Khan, Isha Soni, Preeti Jain, Samriddhi Shukla, Rajeev Yadav, Pratik Sen, Syed M. Meeran, Sanjay Batra

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3485-3499
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number8
DOIs
StatePublished - Apr 23 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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