Synthesis of New Derivatives of Benzofuran as Potential Anticancer Agents

Abstract

The results of our previous research indicated that some derivatives of benzofurans, particularly halogeno-derivatives, are selectively toxic towards human leukemia cells. Continuing our work with this group of compounds we here report new data on the synthesis as well as regarding the physico-chemical and biological characterization of fourteen new derivatives of benzofurans, including six brominated compounds. The structures of all new compounds were established by spectroscopic methods (¹H- and, ¹³C-NMR, ESI MS), and elemental analyses. Their cytotoxicity was evaluated against K562 (leukemia), MOLT-4 (leukemia), HeLa (cervix carcinoma), and normal cells (HUVEC). Five compounds (1c, 1e, 2d, 3a, 3d) showed significant cytotoxic activity against all tested cell lines and selectivity for cancer cell lines. The SAR analysis (structure-activity relationship analysis) indicated that the presence of bromine introduced to a methyl or acetyl group that was attached to the benzofuran system increased their cytotoxicity both in normal and cancer cells.

Keywords: HeLa; K562; MOLT-4; benzofurans; chemical synthesis; cytotoxic properties.

Figure 1

Structures of natural and synthetic benzofuran derivatives with biological activity.

Figure 2

Structures of synthetic benofuran derivatives I–V with anticancer activity [7].

Figure 3

Structures of 2- and 3-benzofurancarboxylic acid derivatives VI–VII with cytotoxic activity.

Figure 4

Structures of the benzofuran derivatives VIII–X, lead compounds used in the present studies.

Scheme 1

Synthesis of analogues of compound VIII.

Scheme 2

Synthesis of analogues of compound IX.

Scheme 3

Synthesis of analogues of compound X.

Figure 5

Activity of caspase 3 and 7 in K562 cells treated with the test benzofurans 1c, 1e, 2d, 3d, or staurosporine for 18 h. Apoptosis was determined by Apo-ONE^® Homogeneous Caspase-3/7 Assay (Promega, Madison, WI, USA). Abbreviations: DMSO—K562 cells treated with 1% DMSO. The caspase activation level in cells exposed to 1% DMSO was normalized to 1.0. Mean values +/− SD are shown.

Figure 6

Digestion of pcDNA3.1HisC (total length 5.5kbp) with BamH1 endonuclease. M—marker DNA; 1—not digested plasmid DNA; 2—plasmid DNA digested with BamH1 (DNA present in linear form); 3—plasmid DNA + daunorubicin + BamH1; 4—plasmid DNA + 1c + BamH1; 5—plasmid DNA + 2d + BamH1; 6—plasmid DNA + 1e + BamH1; and, 7—plasmid DNA + 3d + BamH1.