Thiosemicarbazones: The New Wave in Cancer Treatment

Abstract

The anticancer effects of thiosemicarbazones were once solely attributed to the inhibition of ribonucleotide reductase, an enzyme involved in the rate-limiting step of DNA synthesis. However, the mechanism behind this inhibition was initially not described. The ability of thiosemicarbazones to chelate metal ions has now been recognized as a major factor in their antiproliferative effects. This mini-review discusses current advances of an emerging 'new wave' of thiosemicarbazones as potent anticancer agents, describing recent insights into their mechanism of action. The redox activity of Fe-thiosemicarbazone complexes is critical in their anticancer activity, resulting in oxidative damage and the inhibition of ribonucleotide reductase. In vivo analysis indicates that some thiosemicarbazones show potential as chemotherapeutic agents.

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

“…Since then, several generations of TSCs have been tested for their chemotherapeutic potential (96,108). In early mechanistic studies, the anticancer activity of TSCs was attributed to their ability to inhibit ribonucleotide reductase, an enzyme involved in DNA synthesis and repair (18).…”

“…Among those known to chelate iron and target topoisomerase IIa are dexrazoxane, (E)-N,N-dimethyl-2-(quinolin-2-ylmethylene)hydrazinecarbothioamide (TSC-24), and Dp44mT ( Fig. 3) (18,96,108,209). TSC-24 is considered a catalytic top2a inhibitor due to a direct interaction with the ATPase domain of top2a, which leads to a blockade of ATP hydrolysis.…”

Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells

“…Some studies have revealed that triapine shows considerably higher efficacy than N-hydroxyurea in both enzyme and cell assays. Recent studies also show that some thiosemicarbazone derivatives inhibit topoisomerase II a enzyme [9][10][11][12] . However, some naphthalene derivatives have also been reported as potent apoptosis inducers, P-glycoprotein inhibitors, microtubule inhibitors or glutamamide analogs [13][14][15][16][17][18][19][20][21] .…”

Complexos heterolépticos de ouro(III) com potenciais antitumorais e anti-Trypanosoma cruzi

“…Desta maneira, a replicação de base é dificultada ou impedida de ocorrer e/ou são criadas lesões nas fitas de DNA por ruptura oxidativa [34]. tiossemicarbazonas, envolvendo a inibição da enzima RR [35]. A estabilização da enzima ocasionada pelo centro de ferro não-heme, é essencial para sua atividade catalítica.…”

“…E, na presença do PCT, ocorre a inibição da RR devido à coordenação do composto ao centro metálico de ferro [36]. As células cancerígenas expressam níveis elevados de RR em relação às células normais, devido a sua maior taxa de proliferação e, por este motivo, elas se tornam mais susceptíveis para tal coordenação [35].…”