Piperine analogs arrest c-myc gene leading to downregulation of transcription for targeting cancer

Abstract

G-quadruplex (G4) structures are considered a promising therapeutic target in cancer. Since Ayurveda, Piperine has been known for its medicinal properties. Piperine shows anticancer properties by stabilizing the G4 motif present upstream of the c-myc gene. This gene belongs to a group of proto-oncogenes, and its aberrant transcription drives tumorigenesis. The transcriptional regulation of the c-myc gene is an interesting approach for anticancer drug design. The present study employed a chemical similarity approach to identify Piperine similar compounds and analyzed their interaction with cancer-associated G-quadruplex motifs. Among all Piperine analogs, PIP-2 exhibited strong selectivity, specificity, and affinity towards c-myc G4 DNA as elaborated through biophysical studies such as fluorescence emission, isothermal calorimetry, and circular dichroism. Moreover, our biophysical observations are supported by molecular dynamics analysis and cellular-based studies. Our study showed that PIP-2 showed higher toxicity against the A549 lung cancer cell line but lower toxicity towards normal HEK 293 cells, indicating increased efficacy of the drug at the cellular level. Biological evaluation assays such as TFP reporter assay, quantitative real-time PCR (qRT- PCR), and western blotting suggest that the Piperine analog-2 (PIP-2) stabilizes the G-quadruplex motif located at the promoter site of c-myc oncogene and downregulates its expression. In conclusion, Piperine analog PIP-2 may be used as anticancer therapeutics as it affects the c-myc oncogene expression via G-quadruplex mediated mechanism.

High Value-Added Application of Natural Plant Products in Crop Protection: Construction and Pesticidal Activities of Piperine-Type Ester Derivatives and Their Toxicology Study

“…12 To find new promising pesticide candidates, recently, structural modification of natural bioactive products has received much attention. 13−15 Piperine (1, Figure 1) as a natural alkaloid isolated from the black pepper (Piper nigrum), exhibited a variety of biological properties including anticancer, 16,17 anti-inflammation, 18 anti-Alzheimer's disease (AD), 19 anti-Parkinson's disease (PD), 20,21 antiseizure, 22 antiadipogenic, 23 and insecticidal activities. 24−27 Previously, we found that the ester group can play a key role for improving agrochemical activities, for instance, some of osthole esters (I and II, Figure 1), 28,29 andrographolide esters (III, Figure 1), 30 and limonin esters (IV, Figure 1) 31 showed interesting pesticidal activities.…”

“…Piperine ( 1 , Figure ) as a natural alkaloid isolated from the black pepper (Piper nigrum), exhibited a variety of biological properties including anticancer, , anti-inflammation, anti-Alzheimer’s disease (AD), anti-Parkinson’s disease (PD), , antiseizure, antiadipogenic, and insecticidal activities. − Previously, we found that the ester group can play a key role for improving agrochemical activities, for instance, some of osthole esters ( I and II , Figure ), , andrographolide esters ( III , Figure ), and limonin esters ( IV , Figure ) showed interesting pesticidal activities. In addition, the Vilsmeier–Haack–Arnold (VHA) reaction has frequently been used in the total synthesis of natural products and drugs, and its main function includes aromatic formylation reaction or as a fulcrum for the introduction of different functional groups to obtain target compounds, such as homofascaplysin C and commercial anticarcinogen Sunitinib malate. , Consequently, in this paper we wanted to prepare a series of new piperine-type ester derivatives via the key intermediate aldehyde by application of a VHA formylation reaction of piperine (Figure ).…”

Aberrant expression of KDM1A inhibits ferroptosis of lung cancer cells through up-regulating c-Myc

“…The aberrantly expressed c-Myc, a member of MYC gene family, has been proved to participate in the regulation of multiple biological functions in human cancers 31 . It has been reported that c-Myc could regulate the transcription of targeted genes by binding some histone components 32 . Amente et al showed that c-Myc could directedly bind and recruit KDM1A to the E-box chromatin, promoting the transcriptional activity of target genes 33 .…”

Piperine: Chemistry and Biology

“…Compound 4 ( Figure 2 ) exhibited powerful inhibitory activity with a half-maximal inhibitory concentration (IC 50 ) value of 231 nM [ 37 ]. Pandya et al found that piperine analogue 5 ( Figure 2 ) may serve as an anticancer therapeutic seeing it affects c-myc oncogene expression via G-quadruplex mediated mechanism [ 38 ].…”

“…The SARs analysis of piperine and its derivatives are described in Figure 6 , and the detailed descriptions are as follows: (i) introduction of hydroxyl groups at C-8 and C-9 positions can obtain a potent antiviral candidate [ 38 ]. Replacing the dioxymethylene ring with a 2-oxazoline heterocyclic ring and introducing a Cl atom at the C-10 position can produce an anti-inflammatory agent, which has potent therapeutic effects against neuroinflammation [ 46 ]; (ii) introduction of ester and oxime ester groups at C-2 position of piperine is important for improving acaricidal activity.…”