During the course of our studies aiming for the discovery of new pterocarpan-based antineoplastic and antiparasitary compound, we reported the synthesis of 11a-N-Tosyl-5-deoxi-pterocarpanand analogues (1a-f)   through palladium-catalyzed aza-arylation of dihydronaphtalen or cyclohexadiene respectively, using palladium acetate or COF300@Pd(OAc)2. These compounds showed antineoplastic effect on MDR leukemic cell lines K562, Lucena-1 and FEPS with IC50 2.90 � 0.65, 2.49 � 0.14 and 2.12 � 0.73 respectively. Compound 1a is the most promising antileukemic agent since it was the most active on MDR cells without detectable toxicity to normal immune system cells. This compound promoted the inhibition of DNA proliferation and cell cycle arrest at G2 phase regardless of MDR phenotype.These compounds showed antineoplastic effect on MDR leukemic cell lines (K562, IC50 = 2.90 Lucena-1 and FEPS). Compound 1a  is the most promising antileukemic agent since it was the most active on MDR cells without detectable toxicity to normal immune system cells. This compound promoted the inhibition of DNA proliferation and cell cycle arrest at G2 phase regardless of MDR phenotype. Compound 1a  is also a promising antimalarial. Theoretical results suggest that this compound docks into the binding site of camptothecin and topotecan inside both enzymes selectively in DNA topoisomerase I from Plasmodium falciparum (PfTopoI). PfTopoI is a potential selective target for chemotherapy and drug development against malaria, is used together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Compound 1a  and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. In vitro tests against P.falciparum blood parasites corroborated the theoretical findings since it presented the selectivity index (SI) of 98. In vivo experiments in mice infected with P. berghei showed that 1a  has an antimalarial activity similar to that of chloroquine.

11a-N-Tosyl-5-deoxi-pterocarpan (1a), a promising prototype for targeting MDR leukemia cell lines and DNA topoisomerase I from Plasmodium falciparum (PfTopoI)

248th National Meeting (2014)

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