Design, synthesis and biological evaluation of novel alkyl diamine linked bivalent β-carbolines as angiogenesis inhibitors

Bioorg Med Chem Lett. 2016 Oct 15;26(20):5065-5068. doi: 10.1016/j.bmcl.2016.08.084.

Qing Chen ¹, Wei Chen ², Wenxi Fan ², Liang Guo ², Qin Ma ², Xiaodong Zhang ³, Runlei Du ⁴, Rihui Cao ⁵

Affiliations

1 School of Chemistry and Chemical Engineering, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China.
2 Xinjiang Huashidan Pharmaceutical Co. Ltd, 45 He Nan East Road, Urumqi 830011, PR China.
3 College of Life Sciences, Wuhan University, 299 Ba Yi Road, Wuchang 430072, PR China.
4 College of Life Sciences, Wuhan University, 299 Ba Yi Road, Wuchang 430072, PR China. Electronic address: runleidu@163.com.
5 School of Chemistry and Chemical Engineering, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China. Electronic address: caorihui@mail.sysu.edu.cn.

PMID: 27597243 DOI: 10.1016/j.bmcl.2016.08.084

Abstract

A series of novel alkyl diamine linked bivalent β-carbolines was synthesized and evaluated for antiproliferative activity, inhibition of cell migration and tube formation, and anti-angiogenic activity in vivo. The results showed that most bivalent β-carbolines displayed significant antiproliferative effect against human umbilical vein cell lines EA.HY926. Compound 2s was found to be the most potent antiproliferative agent with IC₅₀ value of 1.06μM against EA.HY926 cell lines. Further investigations on mechanisms of action revealed that compound 2s significantly inhibited EA.HY926 cells migration and tube formation in a dose-dependent manner. Moreover compound 2s exhibited significant angiogenesis inhibitory effects in CAM assay, and the antiangiogenetic potency was comparable with the reference drug Endostar (30μM).

Keywords

Angiogenesis inhibitors; Antitumor; Bivalent β-carbolines; Structure–activity relationships; Synthesis.

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