Furanoditerpenes from Pterodon pubescens benth with selective in vitro anticancer activity for prostate cell line

Abstract

O fracionamento biomonitorado do extrato diclorometânico das sementes de Pterodon pubescens Benth forneceu o 6α-acetóxi-7β-hidróxi-vouacapano 1 (inédito), além de quatro diterpenos furânicos (2, 3, 4 e 5). A atividade antiproliferativa dos compostos foi avaliada in vitro contra as linhagens de células tumorais humanas UACC-62 (melanoma), MCF-7 (mama), NCI-H460 (pulmão), OVCAR-03 (ovário), PC-3 (próstata), HT-29 (colon), 786-0 (rim), K562 (leucemia) e NCI-ADR/RES (ovário com fenótipo de resistência a múltiplos fármacos). Os resultados foram expressos em três concentrações efetivas GI 50 (concentração para que ocorra 50% de inibição de crescimento), TGI (concentração que resulta em inibição total de crescimento) e LC 50 (concentração que resulta em 50% de morte celular). A citotoxicidade in vitro foi avaliada também frente a uma linhagem de célula murina normal (3T3). Este é o primeiro relato de atividade anticâncer para os compostos 1, 4 e 5, que apresentaram grande seletividade, dependente da concentração, para PC-3. O composto 1 foi 26 vezes mais potente para inibir 50% do crescimento (GI 50 ) de PC-3, 15 vezes mais citostático (TGI) e 6 vezes menos tóxico (LC 50 ) quando comparado com Doxorrubicina (controle).Activity guided fractionation of Pterodon pubescens Benth. methylene chloride-soluble fraction afforded novel 6α-acetoxi 7β-hydroxy-vouacapan 1 and four known diterpene furans 2, 3, 4, 5. The compounds were evaluated for in vitro cytotoxic activities against human normal cells and tumour cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-H460 (lung, non-small cells), OVCAR-03 (ovarian), PC-3 (prostate), HT-29 (colon), 786-0 (renal), K562 (leukemia) and NCI-ADR/RES (ovarian expressing phenotype multiple drugs resistance). Results were expressed by three concentration dependent parameters GI 50 (concentration that produces 50% growth inhibition), TGI (concentration that produces total growth inhibition or cytostatic effect) and LC 50 (concentration that produces −50% growth, a cytotoxicity parameter). Also, in vitro cytotoxicity was evaluated against 3T3 cell line (mouse embryonic fibroblasts). Antiproliferative properties of compounds 1, 4 and 5 are herein reported for the first time. These compounds showed selectivity in a concentration-dependent way against human PC-3. Compound 1 demonstrated selectivity 26 fold more potent than the positive control, doxorubicin, for PC-3 (prostrate) cell line based on GI 50 values, causing cytostatic effect (TGI value) at a concentration fifteen times less than positive control. Moreover comparison of 50% lethal concentration (LC 50 value) with positive control (doxorubicin) suggested that compound 1 was less toxic.Keywords: Pterodon pubescens, leguminosae, furanoditerpenes, in vitro assay, prostate cell line, cytotoxicity IntoductionThroughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialized drugs hav...

Terpenic subfraction of Pterodon pubescens induces apoptosis of K562 leukemic cells by modulating gene expression

“…Phytochemical studies of SF5 also indicated the presence of linear diterpenes (geranylgeraniol and farnesol derivatives), and the furane diterpenes 7ß-acetoxy- vouacapan, 6·-7ß-diacetoxyvouacapan-17ß-oate and methyl-6·-acetoxy-7ß-hydroxyvouacapan-17ß-oate (Table I). These compounds were previously reported for Pterodon pubescens (14,16,31). Both linear or cyclic diterpenes may be involved in the apoptotic effect of SF5 on leukemic cells since similar vouacapan diterpenes have induced cytotoxicity and apoptosis of melanoma cells and prostate cancer cell, respectively (17,31), and apoptosis of leukemia U937 cells has been reported to geranylgeraniol (32).…”

Preparation and characterization of microcapsules of Pterodon pubescens Benth. by using natural polymers

“…We also saw absorption at 1244 cm -1 (indicating the asymmetric C-O stretch of acetate), at 1017 cm -1 (indicating asymmetric stretch of the C-O-C ester), and at 732 cm -1 (reflecting furan rings). This trait was also found by Spindola et al (2009) when they analyzed 6α-acetoxy,7β-hydroxy-vouacapan.…”

“…Vouacapans are furanoditerpenes involved in the antirheumatic, antinociceptive, and anti-inflammatory activities of the oil extracted from P. pubescens fruit (Carvalho et al, 1999;Nunan, Carvalho, Piloveloso, 1982;Silva et al, 2004;Spindola et al, 2009;Spindola et al, 2010). Earlier studies by our group have identified the presence of 2 vouacapans in FHPp that may be directly involved in their potential therapeutic activity: methyl 6α-acetoxy-7β-hydroxyvouacapan-17β-oate (vouacapan 3) and methyl 6α-hydroxy-7β-acetoxyvouacapan-17β-oate (vouacapan 4) (Hoscheid et al, 2012).…”

Pterodon pubescens benth: stability study of microencapsulated extract and isolated compounds monitored by antinociceptive assays

“…Furan diterpenes were identified and isolated from Pterodon species. [3][4][5][6][7] Authors have reported that furanoditerpenes possessing vouacapan skeleton are involved with the anti-inflammatory, antinociceptive and antiproliferative properties of Pterodon pubescens seed crude extract. [7][8][9][10][11][12] We previously reported the antinociceptive properties of geranylgeraniol and 6α,7β-dihydroxy-vouacapan-17β-oate methyl ester, compounds isolated from Pterodon pubescens Servat et al 1245 Vol.…”