Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

Abstract

Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a terpenenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation.

Potential Combinational Anti-Cancer Therapy in Non-Small Cell Lung Cancer with Traditional Chinese Medicine Sun-Bai-Pi Extract and Cisplatin

“…The side effects of the traditional treatment methods make them more difficult and less suitable for patients with more advanced stages of cancer or poorer health [ 26 – 29 ]. Based on the side effects and harm caused by these therapies, recent studies focused on the tumor cells and paid more attention to cellular immunotherapy, gene therapy, target drug therapy, etc [ 30 – 34 ]. Some studies tried to apply Chinese herbal medicines to cancer treatment [ 35 – 38 ].…”

Novel polygodial analogs P3 and P27: Efficacious therapeutic agents disrupting mitochondrial function in oral squamous cell carcinoma

“…Therefore, novel therapeutic strategies to target advanced OSCC are required to treat this deadly disease. Thus, the aim of the present study was to synthesize novel polygodial analogs and investigate their cytotoxic effects against multiple drug-resistant cancer cell lines in vitro ( 2 ). Polygodial, a known transient receptor potential vanilloid subtype 1 (TRPV1) agonist, is an unsaturated 1,4-dialdehyde sesquiterpene and the pungent component of peppers such as the Dorrigo pepper, mountain pepper and water pepper ( 3 - 6 ).…”

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

“…32,33 To obtain firm evidence of Paal–Knorr reactivity in these compounds, we attempted to isolate such pyrrole adducts (Scheme 9). Our proposed explanation for the lack of stability of the produced pyrroles was their electron-rich character and, thus, high propensity toward oxidation.…”

“…These agents are capable of overcoming drug resistance in glioblastoma, melanoma and other cancer cells serving as models for tumours typically associated with dismal prognoses. 33 It is noteworthy that such derivatives have a pyrrole-forming reactivity of their own, producing stable adducts, such as 28 via 26 and 27 , when reacted with primary amines. Efforts are now underway to understand the role of this chemistry in cancer and identify their protein targets.…”