Synthesis and Biological Evaluation of 2-aroyl-4-phenyl-5- hydroxybenzofurans as a New Class of Antitubulin Agents

Abstract

Microtubules are among the most successful targets for development of compounds useful for anticancer therapy. Continuing our project to develop new small molecule antitumor agents, two new series of derivatives based on the 2-aroyl-4-phenylbenzofuran molecular skeleton were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. SAR were elucidated with various substitutions on the benzoyl moiety at the 2-position of the benzofuran ring. The most promising compound in this series, the (5-hydroxy-4-phenylbenzofuran-2-yl)(4-methoxyphenyl)methanone derivative (3d), has significant growth inhibitory activity in the submicromolar range against the Molt4, CEM and HeLa cancer cell lines and interacts with tubulin by binding to the colchicine site. Exposure to 3d led to the arrest of K562 cells in the G2-M phase of the cell cycle and to the induction of apoptosis.

Crystal structure of 1-(6-hydroxy-2-phenylbenzofuran-5-yl)ethan-1-one, C16H12O3

“…In addition to their wide range of pharmacological properties, carbo-substituted benzofurans find application as fluorescent sensors and as components of light emitting diodes [6]. The ortho-hydroxyacetyl moiety is prevalent on the framework of naturally occurring benzofurans with useful biological activities such as anticancer, antimicrobial, immunomodulatory, antioxidant and anti-inflammatory properties [7][8][9][10]. Some derivatives also exhibit enzyme inhibitory properties against protein tyrosine phosphatase 1B (PTP-1B) [11,12].…”

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives

“…3) Moreover, a number of furan based compounds exhibited antimicrobial, anticancer, antitumor, anti-inflammatory, and antitubulin activities and are also used for treatment of cardiac arrhythmias. [4][5][6][7][8] Furthermore, it has been explored that the tetrahydrofuryl moiety is a basic structural motif in many important C-glycosides [9][10][11][12] of significant biological and chemical interest. Being a bioisostere of pyrimidine and oxadiazole, thiadiazole compounds have, extensively, found outstanding pharmacological applications.…”

“…H-NMR (DMSO-d6 ) δ/ppm: 3.27 (t, 2H, J = 6.6 Hz, CH 2 ), 3.51 (t, 2H, J = 6.6 Hz, CH 2 ), 4.12 (s, 2H, CH 2 ), 5.29 (m, 2H, NH 2 exchangeable),6.61 (m, 1H, furanH-4), 7.56 (m, 1H, furanH-3), 8.10 (d, 1H, J = 7.6 Hz, furanH-5), 9.17-9.25 (br s, 2H, 2NH exchangeable),9.50 (br s, 1H, NH exchangeable), 10.18 (br s, 1H, NH);13 C-NMR (DMSO-d 6 ) δ: 31.9, 32.4, 33.5 (3CH 2 ), 111.5, 115.3, 143.0, 146.5 (furyl-C), 152, 164 (thiadiazole-C), 157, 170, 173, 177 (4CO); IR (KBr) cm −1 , ν 3430, 3305 (NH, NH 2 ), 2920 (CH), 1658 (C=O), 1615 (CN); MS m/z: 413 (M + , 44%). Anal.…”

Synthesis of Some Aryl Ketoxime Derivatives with their in vitro Anti-microbial and Cytotoxic Activity

“…Meta position was not ideal for the tubulin polimerization. In addition the best antiproliferative activity was showed by (5-hydroxy-4-phenylbenzofuran-2yl) (4-methoxyphenyl) methanone derivative (3d), which was activate sub-micromolar concentrations against Molt/4, CEM and HeLa cancer cell lines [9].…”