Calix[n]arenos como catalisadores em reações orgânicas : síntese e triagem da atividade antiproliferativa in vitro em células tumorais humanas de xantenonas e ftalazinas-triona

Abstract

Calix[n]arenes, macrocyclic compounds of phenolic units linked by methylene groups at 2,6-positions, are widely used as ligands for obtaining organometalic catalysts. Their use as catalysts in absence of metals is, however, poorly explored. This study focused on the synthesis of six calix[n]arenes and their possible use as catalysts inthe synthesis of xanthenones and phthalazines. In the synthesis of xanthenones, p-sulfonic acid calix[4]arene (1.5 mol% in theabsence of solvents) exhibited the highest catalytic efficiency in 1 h-reaction performed with various aromatic aldehydes, -naphthol (or 3,4-methylendioxyfenol) and 1,3-dicarbonyl compounds. Xanthenones were obtained with moderate to good yields (55-92%). This approach allowed obtaining 59 xanthenones that were further investigated for the antiproliferative activity in vitro against human cancer cells. Among xanthenones, compound 12-(4-hydroxy-3,5-dimethoxyphenyl)-10,10-dimethyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (41) presented a broad spectrum of action when used at 10 g/mL, while compound 9,9-dimethyl-12-phenyl-9,10-dihydro-8Hbenzo[a]xanthen-11(12H)-one (5) (GI50 = 0,027 g/mL) was as potent as the reference drug doxorubicin (GI50 = 0,024 g/mL) against drug-resistant ovarian (NCI-ADR/RES) cancer cells. A quantitative structure-activity relationship (QSAR) study was performed and two QSAR models were obtained for compounds of Group 1 against U251 andNCI-H460 cells and indicated that the biological activity of compounds increased with increasing accessible surface area of hydrogen bond donor atoms. In the synthesis of phthalazines, p-sulfonic acid calix[4]arene (1.5 mol% in ethyl lactate) exhibited the highest catalytic efficiency after 10 min of reaction (under microwave irradiation) performed with various aromatic or non-aromatic aldehydes,phthalhydrazide and dimedone. Aromatic aldehydes provided better yields (31-94%) than did non-aromatic ones (11-35%). This approach allowed obtaining 14 phthalazines that were further investigated for the antiproliferative activity against human cancer cells.In general, these compounds proved to be little activity against the tested strains. Phthalazine 3,3-dimethyl-3,4-dihydro-1H-indazolo[2,1-b]phthalazine-1,6,11(2H,13H)-trione (76) was the most promising, with active against drug-resistant ovarian (NCIADR/ RES) and leukemia (K562) cancer cells.The physicochemical properties calculated for the phthalazines-triones shown that this class of compounds can be identified as promising for the development of compounds with antriproliferative activity, however, it is necessary to the synthesis of new structural analogues for a more detailed study of the potential of this class of substances.