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

Thiago A Grigolo; Carolyne B Braga; Catia Ornelas; Dennis Russowsky; Guilherme A Ferreira-Silva; Marisa Ionta; Ronaldo A Pilli

doi:10.1016/j.bioorg.2021.105292

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

Bioorg Chem. 2021 Nov:116:105292. doi: 10.1016/j.bioorg.2021.105292. Epub 2021 Aug 25.

Authors

Thiago A Grigolo¹, Carolyne B Braga¹, Catia Ornelas¹, Dennis Russowsky², Guilherme A Ferreira-Silva³, Marisa Ionta³, Ronaldo A Pilli⁴

Affiliations

¹ Department of Organic Chemistry, Institute of Chemistry, University of Campinas, UNICAMP, 13083-970 Campinas, Sao Paulo, Brazil.
² Institute of Chemistry, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil.
³ Institute of Biomedical Sciences, Federal University of Alfenas, UNIFAL-MG, 37130-001 Alfenas, Minas Gerais, Brazil.
⁴ Department of Organic Chemistry, Institute of Chemistry, University of Campinas, UNICAMP, 13083-970 Campinas, Sao Paulo, Brazil. Electronic address: rapilli@unicamp.br.

PMID: 34509797
DOI: 10.1016/j.bioorg.2021.105292

Abstract

A library of nine hybrids of 4-hydroxygoniothalamin (2), 4-hydroxypiplartine (4), monastrol (5) and oxo-monastrol (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-hydroxypiplartine-based hybrids 12 and 22 displayed high cytotoxicity (IC₅₀ values below 10 μM) against all cancer cells studied, especially in MCF-7 cells with IC₅₀ values of 1.7 ± 0.1 and 1.6 ± 0.9 μM, respectively. Furthermore, the 4-hydroxygoniothalamin-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.

Keywords: Anticancer; Cell cycle analysis; Cytotoxicity; Goniothalamin; Hybrids; Monastrol; Piplartine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Piperidones / chemistry
Piperidones / pharmacology*
Pyrones / chemistry
Pyrones / pharmacology*
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Piperidones
Pyrones
Triazoles
piperlongumine
goniothalamin