Design and Synthesis of N‐Acylated Aza‐Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Abstract

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N-Acylation of aza-goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1-(E)-But-2-enoyl-6-styryl-5,6-dihydropyridin-2(1H)-one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC-3 cells, which was probably a signal for caspase-dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7-aminoactinomycin D double staining, which indicated apoptosis, and also led to G2 /M cell-cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza-goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.

Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice

“…Regarding natural product‐derived compounds, different studies have shown an antitumoral activity in different cancer cell lines treated with compounds such as GTN (de Fátima et al, ). Barcelos et al () verified that compounds derived from GTN presented antiproliferative activity, leading to reactive oxygen species occurrence and apoptosis in the human prostate cancer cells (PC‐3). Also, antiproliferative effects on human renal cancer cells were seen after administering (R)‐GTN and also (S)‐GTN (non‐natural isomer) in vitro (de Fátima et al, ).…”

Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis

“…In particular, inhibition of chronic inflammation, which precedes or accompanies tumor development, has recently come to light as an attractive option. Racemic GTN, a styryl lactone found in its R configuration in plants of the genus Goniothalamus, Annonaceae, has in vitro antiproliferative activity in human tumor cell lines via activation of apoptosis (18)(19)(20)23,38). GTN also presents general anti-inflammatory effects, without side effects (as seen with aspirin, for example) in the therapeutic doses (20,22,39).…”

“…Previous studies performed by our group showed that racemic GTN presents gastroprotective effects, anti-inflammatory activity and inhibits the development of Ehrlich tumor (mammary adenocarcinoma) in mice (19)(20)(21)(22). Recently, we showed that GTN induces apoptosis in HT-29 colon tumor cells, which was dependent on ROS generation and caspase activation (23).…”

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

“…22 Piperlongumine causes an increase in reactive oxygen species (ROS) levels in cancer cells but not in normal cells, 22 and piperlongumine analogues also enhanced ROS in PC-3 cells. 24 This activity may be at least partly due to proteasome inhibition and may be responsible for the selective activity of piperlongumine. 25,26 Nonetheless, few studies to date have investigated the impact of this compound on cell migration.…”