Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents

Autor(es)

Grigolo, Thiago A. ^[1] ; Braga, Carolyne B. ^[1] ; Ornelas, Catia ^[1] ; Russowsky, Dennis ^[2] ; Ferreira-Silva, Guilherme A. ^[3] ; Ionta, Marisa ^[3] ; Pilli, Ronaldo A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Chem, Dept Organ Chem, UNICAMP, BR-13083970 Campinas, SP - Brazil

^[2] Univ Fed Rio Grande do Sul, Inst Chem, BR-91501970 Porto Alegre, RS - Brazil

^[3] Univ Fed Alfenas, Inst Biomed Sci, UNIFAL MG, BR-37130001 Alfenas, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOORGANIC CHEMISTRY; v. 116, NOV 2021.
• Citações Web of Science: 0

Resumo

A library of nine hybrids of 4-hydroxygoniothalamin (2), 4-hydroxypiplartine (4), monastrol (5) and oxomonastrol (6) was prepared via a modular synthetic route with a diester or a 1,2,3-triazole as linkers. The compounds were assayed against a panel of human cancer cell lines, including MCF-7 (breast adenocarcinoma), HeLa (cervical adenocarcinoma), Caco-2 (colorectal adenocarcinoma) and PC3 (prostate adenocarcinoma), as well as against normal breast (MCF10A) and prostate (PNT2) cells. In general, hybrids with an ester linker containing 4-hydroxypiplartine (4) were more potent than the corresponding hybrids with 4-hydroxygoniothalamin (2). On the other hand, compounds presenting the 1,2,3-triazole linker displayed enhanced cytotoxicity and selectivity when compared to their corresponding hybrids with the diester linker. The 4-hydroxypiplartinebased hybrids 12 and 22 displayed high cytotoxicity (IC50 values below 10 mu M) against all cancer cells studied, especially in MCF-7 cells with IC50 values of 1.7 +/- 0.1 and 1.6 +/- 0.9 mu M, respectively. Furthermore, the 4hydroxygoniothalamin-monastrol hybrid (compound 21) and the 4-hydroxypiplartine-oxo-monastrol hybrid (compound 25), both bearing a 1,2,3-triazole linker, displayed high selectivity and potency towards breast cancer cell line (MCF-7 vs. MCF10 cells, selectivity index = 15.8 and 7.1, respectively), while the 4-hydroxypiplartine -4-hydroxymethylgoniothalamin hybrid with a diester linker (compound 33) showed high selectivity towards melanoma cancer cells (selectivity index = 9.6). Antiproliferative and pro-apoptotic potential of compounds 12 and 22 against MCF-7 cancer cells were further investigated. Cell cycle studies revealed increased G2/ M population in MCF-7 cultures as well as reduced G0/G1 population compared to the control groups indicating cell cycle arrest in G2/M phase. In addition, the frequency of positive cells for annexin V was higher in treated samples suggesting that compounds 12 and 22 induce apoptosis in estrogen-positive MCF-7 cells. (AU)

• Processo FAPESP: 17/06146-8 - Desenvolvimento de nanocarregadores baseados em dendrímeros e nanopartículas poliméricas para a vetorização seletiva da goniotalamina, piplartina e monastrol
• Beneficiário: Carolyne Brustolin Braga
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/02093-0 - Desenvolvimento de novos nanomateriais para aplicações em nanomedicina
• Beneficiário: Cátia Cristina Capêlo Ornelas Megiatto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/13104-5 - Planejamento e síntese de inibidores baseado em alvo biológico: o caso das quinases negligenciadas
• Beneficiário: Ronaldo Aloise Pilli
• Modalidade de apoio: Auxílio à Pesquisa - Regular