Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

Anne Cecília Nascimento da Cruz (1) , Dalci José Brondani (1) , Temístocles Ítalo de Santana (1) , Lucas Oliveira da Silva (1) , Elizabeth Fernanda da Oliveira Borba (1) , Antônio Rodolfo de Faria (1) , Julianna Ferreira Cavalcanti de Albuquerque (1) , Sylvie Piessard (2) , Rafael Matos Ximenes (1) , Blandine Baratte (3, 4, 5) , Stéphane Bach (6, 4, 5) , Sandrine Ruchaud (6) , Francisco Jaime Bezerra Mendonça Junior (7) , Marc-Antoine Bazin (2) , Marcelo Montenegro Rabello (1) , Marcelo Zaldini Hernandes (1) , Pascal Marchand (2) , Teresinha Gonçalves da Silva (1)

1 UFPE - Universidade Federal de Pernambuco [Recife]
2 IICiMed - Cibles et Médicaments des Infections et de l'Immunité - EA 1155
3 LBI2M - Laboratoire de Biologie Intégrative des Modèles Marins
4 FR2424 - Fédération de recherche de Roscoff
5 SBR - Station biologique de Roscoff = Roscoff Marine Station
6 P3H - Phophorylation de protéines et Pathologies Humaines
7 UFPB - Universidade Federal da Paraiba / Federal University of Paraiba

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC 50 values of 13.08 µM and 11.38 µM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 µM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 µM).

Mots clés: semicarbazones; cytotoxicity; anticancer activity; cell cycle; apoptosis; kinase inhibition

Domaines: Chimie thérapeutique; Cancer

Anne Cecília Nascimento da Cruz, Dalci José Brondani, Temístocles Ítalo de Santana, Lucas Oliveira da Silva, Elizabeth Fernanda da Oliveira Borba, et al.. Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents. Pharmaceuticals, 2019, 12 (4), pp.169. ⟨10.3390/ph12040169⟩. ⟨hal-03864455v2⟩