当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization.

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization.

Abstract：

:The discovery of 3-methoxy-9-(30,40,50-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 lM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 lM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Herdman CA,Devkota L,Lin CM,Niu H,Strecker TE,Lopez R,Liu L,George CS,Tanpure RP,Hamel E,Chaplin DJ,Mason RP,Trawick ML,Pinney KG

doi

10.1016/j.bmc.2015.10.012

subject

Has Abstract

pub_date

2015-12-15 00:00:00

pages

7497-520

issue

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)30090-0

journal_volume

pub_type

杂志文章

在线工具

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization.