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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Dighe SU,Khan S,Soni I,Jain P,Shukla S,Yadav R,Sen P,Meeran SM,Batra S

doi

10.1021/acs.jmedchem.5b00016

subject

Has Abstract

pub_date

2015-04-23 00:00:00

pages

3485-99

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

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