Issue 7, 2018

Discovery of a tetrazolyl β-carboline with in vitro and in vivo osteoprotective activity under estrogen-deficient conditions

Abstract

β-Carbolines have been assessed for osteoclastogenesis. However, their effect on osteoblasts during estrogen deficiency is still unclear. Here, a series of novel piperazine and tetrazole tag β-carbolines have been synthesized and examined for osteoblast differentiation in vitro. In vitro data suggest that compound 8g is the most promising osteoblast differentiating agent that was evaluated for in vivo studies. Compound 8g promoted osteoblast mineralization, stimulated Runx2, BMP-2 and OCN expression levels, increased BrdU incorporation and inhibited generation of free radicals as well as nitric oxide. Since a piperazine group is involved in bone repair activity and β-carboline in IκB kinase (IKK) inhibition, compound 8g inhibited tumor necrosis factor α (TNFα) directed IκBα phosphorylation, preventing nuclear translocation of NF-κB thereby alleviating osteoblast apoptosis. In vivo studies show that compound 8g was able to restore estrogen deficiency-induced bone loss in ovariectomized rats without any toxicity, thus signifying its potential in bone-protection chemotherapy under postmenopausal conditions.

Graphical abstract: Discovery of a tetrazolyl β-carboline with in vitro and in vivo osteoprotective activity under estrogen-deficient conditions

Supplementary files

Article information

Article type
Research Article
Submitted
27 Feb 2018
Accepted
02 Jun 2018
First published
12 Jun 2018

Med. Chem. Commun., 2018,9, 1213-1225

Discovery of a tetrazolyl β-carboline with in vitro and in vivo osteoprotective activity under estrogen-deficient conditions

A. Karvande, S. Khan, I. Khan, D. Singh, V. Khedgikar, P. Kushwaha, N. Ahmad, P. Kothari, A. Dhasmana, R. Kant, R. Trivedi and P. M. S. Chauhan, Med. Chem. Commun., 2018, 9, 1213 DOI: 10.1039/C8MD00109J

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