Synthesis and Cytotoxic Evaluation of Homoveratrylamine-Based Derivatives Derived from Carboxylic Acids
Аннотация
Condensation reactions between homoveratrilamine and various carboxylic acids provide an efficient route to structurally diverse amide and isoquinoline derivatives with potential biological activity. In this study, a series of amides and 1-substituted dihydro- and tetrahydroisoquinolines were synthesized from homoveratrilamine and itaconic acid, mandelic acid, cinnamic acid, m-iodobenzoic acid, 2,4-dinitrobenzoic acid, and 2,4-dichlorobenzoic acid. Amides (4, 5, and 12) and 1-substituted dihydro- (6, 13-16) and tetrahydroisoquinolines (17) were successfully obtained. The cytotoxic activity of the synthesized compounds was evaluated in vitro using the MTT assay against four human cancer cell lines cervical carcinoma (HeLa), mammary adenocarcinoma (HBL-100), laryngeal adenocarcinoma (HEp-2), and T-lymphoblastic leukemia (CCRF-CEM) as well as three non-malignant cell lines, including African green monkey kidney (Vero B) cells, rat embryonic fibroblasts, and rat hepatocytes. The antitumor drug cisplatin was used as a positive control. Proliferative activity was identified for dihydroisoquinolines differing in substituents in the aromatic moiety. This effect emerged and increased in the following order: iodophenyl < dichloro < dinitro < dimethoxy. The transition from dihydroisoquinoline 15 to tetrahydroisoquinoline 17, while retaining the iodophenyl fragment in the structure, also led to the appearance of proliferative properties in cervical carcinoma cells, resulting in an 18% increase in proliferation. Among all tested derivatives, the itaconic acid-based dihydroisoquinolines 6 exhibited the most pronounced cytotoxic activity against HeLa, HBL-100, and HEp-2 cells, with IC₅₀ values of 24.9, 13.1, and 27.1 μM, respectively. Notably, it exhibited considerably lower cytotoxicity toward Vero B cells and hepatocytes, with IC₅₀ values of 95.9 and 100 μM, respectively; however, it proved to be highly toxic to skin fibroblasts (IC₅₀ = 12.6 μM). These results indicate that the itaconic acid dihydroisoquinoline derivative demonstrates pronounced selective cytotoxicity toward cancer cells while largely sparing normal cells, highlighting its potential as a promising lead compound for further optimization.