Synthesis and in vitro anticancer activities of substituted N-(4'-Nitrophenyl)-L-prolinamides

<p>Prolinamides are present in secondary metabolites and have wide-ranging biological properties as well as antimicrobial and cytotoxic activities.</p> <p><i>N</i>-(4'-substituted phenyl)-<b>L</b>-prolinamides <b>4a</b>–<b>4w</b> were synthesised in two steps, starting from the condensation of <i>p</i>-fluoronitrobenzene <b>1a</b>–<b>1b</b> with <b>L</b>-proline <b>2a</b>–<b>2b</b>, under aqueous–alcoholic basic conditions to afford <i>N</i>-aryl-<b>L</b>-prolines <b>3a</b>–<b>3c</b>, which underwent amidation via a two-stage, one-pot reaction involving SOCl₂ and amines, to furnish <b>L</b>-prolinamides in 20–80% yield.</p> <p>The cytotoxicities of <b>4a</b>–<b>4w</b> against four human carcinoma cell lines (SGC7901, HCT-116, HepG2 and A549) were evaluated by MTT assay; with good tumour inhibitory activities (79.50 ± 1.24%–50.04 ± 1.45%) against HepG2. <b>4a</b> exhibited the best antitumour activity against A549 with % cell inhibition of 95.41 ± 0.67% at 100 µM. Likewise, <b>4s</b> (70.13 ± 3.41%) and<b> 4u</b> (83.36 ± 1.70%) displayed stronger antineoplastic potencies against A549 than the standard, 5-fluorouracil (64.29 ± 2.09%) whereas <b>4a</b> (93.33 ± 1.36%) and <b>4u</b> (81.29 ± 2.32%) outperformed the reference (81.20 ± 0.08%) against HCT-116. SGC7901 showed lower % cell viabilities with <b>4u</b> (8.02 ± 1.54%) and <b>4w</b> (27.27 ± 2.38%). These results underscore the antiproliferative efficacies of <b>L</b>-prolinamides whilst exposing <b>4a</b> and <b>4u</b> as promising broad-spectrum anticancer agents. SAR studies are discussed.</p>