Synthesis and in vitro anticancer activities of substituted N-(4′-nitrophenyl)-l-prolinamides

Abstract

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

Keywords

• anti-cancer agents
• biomolecules
• carcinoma cell lines
• cytotoxicity
• pyrrolidine-2-carboxamides