New pterocarpanquinones: Synthesis, antineoplasic activity on cultured human malignant cell lines and TNF-α modulation in human PBMC cells

Abstract

A new pterocarpanquinone (5a) was synthesized through a palladium catalyzed oxyarylation reaction and was transformed, through electrophilic substitution reaction, into derivatives 5b-d. These compounds showed to be active against human leukemic cell lines and human lung cancer cell lines. Even multidrug resistant cells were sensitive to 5a, which presented low toxicity toward peripheral blood mononuclear cells (PBMC) cells and decreased the production of TNF-alpha by these cells. In the laboratory these pterocarpanquinones were reduced by sodium dithionite in the presence of thiophenol at physiological pH, as NAD(P)H quinone oxidoredutase-1 (NQO1) catalyzed two-electron reduction, and the resulting hydroquinone undergo structural rearrangements, leading to the formation of Michael acceptors, which were intercepted as adducts of thiophenol. These results suggest that these compounds could be activated by bioreduction.

LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells

“…The possibility that LQB-118 was cytotoxic by acting as a precursor of reactive oxygen species leading to oxidative stress seemed unlikely, as K562 and K562-Lucena are extremely resistant to oxidative stress [17]. The oxidative stress sensitive leukemic cell HL-60 has been shown to be more sensitive than K562 [18].…”

“…Among these alternative mechanisms, the clinical resistance of CML patients to imatinib can also be atributed to the overexpression of ABC transporters, such as Pgp [11], which was responsible for the efflux of drugs and, therefore, reducing their clinical efficacy. The present study examined in the CML cell line K562 and its multidrug resistant counterpart K562-Lucena [18,19], the effect of a new compound, the pterocarpanquinone LQB-118 [17]. The compound LQB-118 induced, in both cell lines, a decrease in metabolic activity, probably reflecting cell death.…”

“…Recently, it was possible to obtain the synthesis of new pterocarpanquinones, and one such molecule, known as LQB-118, was shown to be effective against leukemic cell lines displaying low toxicity towards peripheral blood mononuclear cells from healthy donors [17]. Although the mode of action of this pterocarpanquinone is still unknown, the para-quinone moiety present in the structure of LQB-118 can participate in the redox cycle in the cell, acting as a precursor of reactive oxygen species and leading to oxidative stress.…”

“…Although the mode of action of this pterocarpanquinone is still unknown, the para-quinone moiety present in the structure of LQB-118 can participate in the redox cycle in the cell, acting as a precursor of reactive oxygen species and leading to oxidative stress. Alternatively, LQB-118 can be activated in situ by reduction, leading to conjugated intermediates, which are powerful alkylating agents [17].…”

Theoretical and Experimental Studies of New Modified Isoflavonoids as Potential Inhibitors of Topoisomerase I from Plasmodium falciparum

“…Although the human Topo I ( Hss TopoI) presents 42% of similarity with P. falciparum Topo I ( Pf TopoI) [11], this enzyme may represent a potential selective target to be explored for drug development against malaria, the aim of our present work. We used docking, molecular dynamics and experimental assays with six synthetic isoflavonoid derivatives, shown in Figure 1 [12]–[14], in comparison to the known Topo I inhibitors camptothecin and topotecan [15]–[17]. Four are pterocarpanquinones (LQB118, LQB216, LQB221, and LQB222), one is N-tosyl-azapterocarpanquinone (LQB192), and one is N-tosyl-azapterocarpan (LQB223).…”