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

Abstract

Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC 50 of 3.0 ± 1.0 µM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC 50 of 1.5 ± 1 µM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4. Keywords: piperlongumine, piplartine, piperamide, cytotoxicity, cell migration inhibition IntroductionMetastasis is the process by which undifferentiated cancer cells migrate to other parts of the body.1,2 Suppression of metastasis is an urgent need in cancer treatment, as most existing drugs only inhibit cell proliferation.3 Traditionally, chemotherapy is based on cytotoxic therapeutic agents that inhibit proliferation and cause cell death. However, the strategy of inhibiting cell migration has recently gained considerable interest. 4 Several compounds that inhibit the process of metastasis have been described to date. 5,6 Paclitaxel, which was originally discovered as an antimitotic agent that disrupts the cell cycle in cancer cells by stabilizing microtubules, exhibits marked and selective inhibition of tumor cell migration. 7As extensively reviewed elsewhere, biodiversity in nature has provided unique chemical scaffolds that have been used as templates for medicinal chemistry and drug discovery. [8][9][10][11][12][13] The availability of natural compound libraries is of significant importance for integrating natural products and medicinal chemistry, especially for the identification of new bioactive agents and the rational design of compounds in drug discovery.14 Within this context, we selected the natural product piperlongumine (1), also known as piplartine, from cell-based assay screening of NuBBE Database (NuBBE DB ) 15 and evaluated its ability to inhibit Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration J. Braz. Chem. Soc. 476 cancer cell migration using biological and target-based experiments.Piperlongumine (1, Figure 1) is an alkamide isolated from several species of Piper (Piperaceae). 16 It is described as possessing antifungal properties, 17 cytotoxicity toward several cancer cell lines, 18,19 and trypanocidal effects, 20 as well as other biological activities. 21 Furthermore, piperlongumine selectively induces cell death in cancer cells but does not reduce viability in normal cells. 22This ...

Piperlongumine and some of its analogs inhibit selectively the human immunoproteasome over the constitutive proteasome

“…Conversely, the simplified R group that retained the aliphatic eNHCO-CH 2 ¼CH 2 motif increased the inhibitory potency by a factor of 5.8. This higher efficiency of 4 on iCP corroborates its higher efficiency against MDA-MB-231 breast cancer cell migration analyzed using the Boyden chamber assay (EC 50 of 1.5 ± 1 mM for 4 and of 3.0 ± 1.0 mM for 1) [3]. These results highlight the favorable role to inhibit iCP of the smaller aliphatic eNHCO-CH 2 ¼CH 2 group compared to the lactam piperidonic ring in 1.…”

“…We thus examined the effect of ring isomerism by replacing the PL d-valerolactam cyclic ring by the known nucleophile trap succinimide (compound 2) or by a non-reactive more expanded bicycle (compound 3) whereas the pharmacophore involving the C7-C8 olefin was conserved. Compound 4 showed a molecular simplification with the conserved Michael acceptor C7-C8 and double bond C2-C3, but the lactam (piperidonic) ring was removed and replaced by a linear vinyl keto group [3]. We demonstrated that the human cCP is poorly inhibited by the tested compounds whereas iCP is efficiently inhibited by 1 and two of its analogs.…”

“…In the other hand, the interference of N-acetyl-Lcysteine with PL suggested that PL displays proteasome inhibitory properties [19]. In this paper, we re-examine the interaction of PL with proteasome by analyzing the inhibitory effect of PL and three of its newly synthesized analogs [3] (Fig. 1B) not only on human cCP but also human iCP.…”

“…The natural PL molecule induces apoptosis in osteosarcoma, breast, bladder and lung cancer cells, but importantly not in normal cells [2]. A potent inhibition of breast cancer cell line migration was observed with PL analogs [3]. PL increases reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, with little effect in primary normal cells [4].…”

Current research on anti-breast cancer synthetic compounds

“…5) was the most active of the series, with an EC 50 of 1.5 AE 1 mM. 113 A series of novel substituted pyridopyrazine derivatives have been rationally designed and evaluated as multi-kinase inhibitors in the PI3K pathway. The most potent compound 134 (Fig.…”