2-Cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenylpropanamido)benzamides: Synthesis, antiproliferative activity, and mechanism of action

Abstract

Several new benzamides 4a–q were synthesized by stirring in pyridine the acid chlorides 3a–q with the appropriate anthranilamide derivatives 2a–g. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of 5 human cell lines (K562 human chronic myelogenous leukemia cells, MCF-7 breast cancer cells, HTC-116 and HT26 colon cancer cells and NCI H460 non-small cell lung cancer cells).

Synthesis, antiproliferative activity and possible mechanism of action of novel 2-acetamidobenzamides bearing the 2-phenoxy functionality

“…As for the previously reported benzamide analogs, 7,8 our data (Table 1) showed positive effects following substitution at the 5 position of the benzamido moiety ( 17f, 17j, 17m, 17r and 17u , Table 1), especially when the substituent(s) was iodine or 4,5-dimethoxy (compounds 17j and 17u , Table 1). Moreover, it seems that the simultaneous introduction of a substituent into both the benzamido and phenoxyacetamido moieties is unfavourable for inhibition of K562 cell growth relative to the unsubstituted 2-cinnamamidobenzamide 4 (Fig.…”

“…In particular, the average inhibitory activity at 10 μM on K562 cell growth, showed by all the previously tested compounds, 7,8 was about 46% 7 and 44%, 8 respectively, while with the phenoxyacetamido moiety, average inhibition was 49%. Moreover, shifting the phenoxyacetamido moiety from the ortho (compound 17a ) to the para or meta position (compounds 21 and 22 , Table 1) resulted in reduced activity.…”

“…The 4-(2-phenoxyacetamido)benzamide ( 21 ) and the 3-(2-phenoxyacetamido)benzamide ( 22 ) were obtained, following the same synthetic route reported for compounds 17a–v , first by transformation of the commercially available nitrobenzoyl chlorides 18a,b to nitrobenzamides 19a,b, 7,8 then by reduction with palladium on activated charcoal in a Parr apparatus (Scheme 2). …”

“…This omission led us to explore the potential of this class of compounds as anticancer agents by synthesizing and screening for antileukemic activity a series of novel 2-cinnamamido, 2-(3-phenylpropiolamido) and 2-(3-phenylpropanamido)benzamides. 7,8 Among the synthesized compounds, 1–5 showed the best antiproliferative activity (Fig. 1).…”

“…Thus, following our studies in the new anticancer agents, 14–17 and on the basis of our previous work on acetamidobenzamides, 7,8 as well as of data reported for some active compounds containing the phenoxyacetamido scaffold, 9–13 we decided to investigate the influence of the cinnamamido and 3-phenylpropiolamido scaffolds when substituted for the phenoxyacetamido scaffold. Moreover, the displacement of the 2-phenoxyacetamido moiety from the ortho to the para and meta positions was investigated.…”