Duas séries de 4-aril-3,4-diidropirimidin-2(1H)-(tio)onas incluindo monastrol (1a), foram sintetizadas por uma metodologia não agressiva ao meio ambiente baseada no uso combinado de ácido cítrico ou ácido oxálico na presença de TEOF (ortoformato de trietila). A atividade como inibidores da proliferação celular da quimioteca de compostos foi avaliada em duas linhagens de gliomas (U138-MG-humana e C6-rato). Os compostos derivados da tiouréia 1f e 1d mostraram atividade citotóxica maior do que a do monastrol. O composto derivado da uréia 2d apresentou a maior atividade citotóxica dentre todos os compostos analisados.Two series of 4-aryl-3,4-dihydropyrimidin-2(1H)-(thio)ones including monastrol (1a), have been synthesized by an environment-friendly methodology based on the combined use of citric acid or oxalic acid and TEOF (triethylorthoformate). The library was evaluated as inhibitor of cell proliferation on two glioma cell lines (human-U138-MG and Rat-C6). The compounds derived from thiourea 1f and 1d were more cytotoxic than monastrol. The compound derived from urea 2d showed the highest cytotoxic activity among the analyzed compounds.Keywords: dihydropyrimidin-2(1H)-ones, Biginelli reaction, triethylorthoformate, TEOF, monastrol, cancer, glioma
IntroductionThe 4-aryl-3,4-dihydropyrimidin-2(1H)-ones (DHPMs) are a class of compounds that has a huge interest in the medicinal chemistry community in recent years.Using high throughput screening (HTS) Mayer et al.1 have evaluated a library of 16,330 small molecules that vary in functional groups and charge. These findings have lead to discover a small molecule which they named monastrol, whose acts by inhibiting the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. This revealed the potential of this compound as antitumor prototype and since that, some SAR (structure activity relationship) studies concerning this interaction have been performed. 9 This set of potentialities linked to the possibility of chemical modulation in all positions of the dihydropirimidinone/thione rings make DHPMs a privileged structure, justifying the great interest in their synthesis.The original three component reaction of DHPMs consisted of a simple one-pot condensation of benzaldehyde 4b, ethyl acetoacetate 5 and urea 6b (Schemes 1 and 2), catalyzed by few drops of hydrochloric acid under refluxing In this context, we have reported the synthesis of a small library of DHPM, including monastrol (1a), using a Lewis acid as catalyst and this series was evaluated against seven human cancer cell lines. 21 The results showed that the oxo-monastrol analogue (2a) just shows cytostatic activity, while monastrol (1a) was cytotoxic against the seven cancer cell lines. We have also found that the 3,4-methylenodioxy derivative (piperastrol, 1c) was approximately 30 times more potent than monastrol (1a) against five of the seven tested cancer cell lines, and it was also more potent than the positive control doxorrubicine against three of the tested cell lines (Figur...
