Design, synthesis and biological evaluation of matrine-dithiocarbamate hybrids as potential anticancer agents

• Published in: European journal of medicinal chemistry Vol. 254; p. 115375
• Main Authors: Zhang, Meng-Wei, He, Yu, Wei, Meng-Xue
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.06.2023; Elsevier
• Subjects: Anticancer drugs; Antineoplastic Agents - pharmacology; Apoptosis; Biological activity; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Chemistry, Medicinal; Dithiocarbamate; Drug Design; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Liver Neoplasms; Matrine; Matrines; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Synthesis; Vincristine - pharmacology; Anticancer drugs; Dithiocarbamate; Matrine; Synthesis; Biological activity; BRASSININ; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115375

A series of novel matrine-dithiocarbamate (DTC) hybrids were efficiently synthesised from matrine through a three-step sequence involving basic hydrolysis, esterification, and DTC formation. They were evaluated for their in vitro cytotoxic potency on several human cancer and normal cells. All matrine-DTC hybrids were much more toxic against the human hepatoma cell line HepG2 than the parent matrine. Hybrid 4l (IC50 = 31.39 μM) was the most potent compound against HepG2 cells, being 156- and 3-fold more toxic than matrine (IC50 > 4900 μM) and the reference vincristine (VCR, IC50 = 93.67 μM), respectively. Moreover, hybrid 4l was less toxic to normal human embryonic kidney cell line HEK-293T, with a higher selectivity index (SI, HEK-293T/HepG2 ≈ 6) than matrine (SI ≈ 1) and VCR (SI ≈ 1). The structure-activity relationship analysis indicated that selectivity was greatly boosted when 4-(trifluoromethyl)benzyl was incorporated into the hybrids (4f and 4l). In addition, the hybrid 4l was also highly toxic to the other five types of human cancer cells (Calu-1, SK-BR-3, HUH-7, 786-O and SK-OV-3; IC50 = 44.18–112.19 μM), whereas it was relatively less toxic to the corresponding normal cells (WI-38, LX-2, HEK-293T and KGN; IC50 = 81.48–195.17 μM). Further mechanistic studies showed that hybrid 4l induced apoptosis in a concentration-dependent manner in HepG2 cells. Our results demonstrate that the cytotoxic activity of matrine can be highly enhanced by hybridisation with DTC. Hybrid 4l has promising applications in anticancer drug development. [Display omitted] •Twelve matrine-dithiocarbamate hybrids were efficiently synthesised from matrine.•All matrine-DTC hybrids were much more toxic to cancer cells HepG2 than matrine.•Hybrid 4l showed 156-fold more toxic than matrine against cancer cells HepG2.•Selectivity was greatly boosted when 4-(trifluoromethyl)benzyl was incorporated.•Apoptosis of HepG2 cells was induced in a concentration-dependent manner by 4l.