Piperlongumine and its derivatives against cancer: A recent update and future prospective

Abstract

Piperlongumine, or piplartine (PL), is a bioactive alkaloid isolated from Piper longum L. and a potent phytoconstituent in Indian Ayurveda and traditional Chinese medicine with a lot of therapeutic benefits. Apart from all of its biological activities, it demonstrates multimodal anticancer activity by targeting various cancer‐associated pathways and being less toxic to normal cells. According to their structure–activity relationship (SAR), the trimethylphenyl ring (cinnamoyl core) and 5,6‐dihydropyridin‐2‐(1H)‐one (piperdine core) are responsible for the potent anticancer activity. However, it has poor intrinsic properties (low aqueous solubility, poor bioavailability, etc.). As a result, pharmaceutical researchers have been trying to optimise or modify the structure of PL to improve the drug‐likeness profiles. The present review selected 26 eligible research articles on PL derivatives published between 2012 and 2023, followed by the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) format. We have thoroughly summarised the anticancer potency, mode of action, SAR and drug chemistry of the proposed PL‐derivatives against different cancer cells. Overall, SAR analyses with respect to anticancer potency and drug‐ability revealed that substitution of methoxy to hydroxyl, attachment of ligustrazine and 4‐hydroxycoumarin heterocyclic rings in place of phenyl rings, and attachment of heterocyclic rings like indole at the C7‐C8 olefin position in native PL can help to improve anticancer activity, aqueous solubility, cell permeability, and bioavailability, making them potential leads. Hopefully, the large‐scale collection and critical drug‐chemistry analyses will be helpful to pharmaceutical and academic researchers in developing potential, less‐toxic and cost‐effective PL‐derivatives that can be used against different cancers.