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

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.

Meta-substituted piperlongumine derivatives attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis.

Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1-3 and 1-6, in which γ-butyrolactam replaced α,ß-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1-3 and 1-6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1-3 or 1-6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1-3 and 1-6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.

Design, synthesis, and evaluation of cytotoxic activities of arylnaphthalene lignans and aza-analogs.

A concise and versatile synthetic strategy for the total synthesis of arylnaphthalene lignans and aza-analogs was developed. The main objective was to develop synthetic tactics for the creation of the lactone and lactam unit that would give access to an array of synthetic, natural, and/or bioactive compounds through rather simple chemical manipulation. The flexibility and potentiality of these new processes were further illustrated by the total synthesis of retrojusticidin B (13b), justicidin C (14b), and methoxy-vitedoamine A (22a). In this study, a series of novel aryl-naphthalene lignans and aza-analogs were synthesized, and the cytotoxic activities of all compounds on cancer cell growth were evaluated. The target compounds were structurally characterized by 1 H NMR (nuclear magnetic resonance), 13 C NMR, infrared, high-resolution mass spectrometry, and X-ray crystallography. The IC50 values of these compounds on five tumor cell lines (A549, HS683, MCF-7, SK-MEL-28, and B16-F1) were obtained by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay. Five of the compounds exhibited excellent activity compared to 5-fluorouracil and etoposide against the five cell lines tested, with IC50 values ranging from 1 to 10 µM.

Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling.

The natural products piperlongumine and piperine have been shown to inhibit cancer cell proliferation through elevation of reactive oxidative species (ROS) and eventually cell death, but only have modest cytotoxic potencies. A series of 14 novel phenylallylidenecyclohexenone analogues based on piperlongumine and piperine therefore were designed and synthesized, and their pharmacological properties were evaluated. Most of the compounds produced antiproliferative activities against five human cancer cells with IC50 values lower than those of piperlongumine and piperine. Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 µM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 µM). Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU. Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP), and induced autophagy in Bel-7402/5-FU cells via regulation of autophagy-related proteins LC3, p62, and beclin-1. Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways. In conclusion, 9m could be a promising candidate for the treatment of drug-resistant cancer cells and, as such, warrants further investigation.

Design, synthesis, and biological evaluation of a novel indoleamine 2,3-dioxigenase 1 (IDO1) and thioredoxin reductase (TrxR) dual inhibitor.

Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor (ZC0101) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101's antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.

Design and Green Synthesis of Piperlongumine Analogs and Their Antioxidant Activity against Cerebral Ischemia-Reperfusion Injury.

The supplementation of exogenous antioxidants to scavenge excessive reactive oxygen species (ROS) is an effective treatment for cerebral ischemia-reperfusion injury (CIRI) in stroke. Piperlongumine (PL), a natural alkaloid, has a great potential as a neuroprotective agent, but it also has obvious toxicity. Moreover, its neuroprotective effects remain to be improved. In this study, we designed a series of novel PL analogs by hybridizing the screened low-toxicity diketene skeleton with antioxidant effect and the 3,4,5-trimethoxyphenyl group, which may increase the antioxidant activity of PL. The intermediate was synthesized by a novel green synthesis method, and 34 compounds were obtained. The compounds without obvious cytotoxicity have remarkable antioxidant effects, especially compared with diketene skeletons and PL. The cytoprotection of the active compound decreased significantly by reduction of the carbon-carbon double bonds of the Michael acceptor in the diketene skeleton. More importantly, further study revealed that compound A9, which has the best activity, can confer protection for cells against oxidative stress and attenuate brain injury in vivo. Overall, this study provided a promising drug candidate for the treatment of CIRI and guided the further development of drug research in oxidative stress-mediated diseases.

Piperlongumine (piplartine) as a lead compound for anticancer agents - Synthesis and properties of analogues: A mini-review.

Piperlongumine, also known as piplartine, is an amide alkaloid of Piper longum L. (long piper), a medical plant known from Ayurvedic medicine. Although was discovered well over fifty years ago, its pharmacological properties have been uncovered in the past decade. In particular, piperlongumine has been most extensively studied as a potential anticancer agent. Piperlongumine has exhibited cytotoxicity against a broad spectrum of human cancer cell lines, as well as demonstrated antitumor activity in rodents. Piperlongumine has also been found to be a proapoptotic, anti-invasive, antiangiogenic agent and synergize with modern chemotherapeutic agents. Because of its clinical potential, several studies were undertaken to obtain piperlongumine analogues, which have exhibited more potent activity or more appropriate drug-like parameters. In this review, the synthesis of piperlongumine analogues and piperlongumine-based hybrid compounds, as well as their anticancer properties and the molecular basis for their activity are explored. General structure-activity relationship conclusions are drawn and directions for the future research are indicated.

Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation.

Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,ß-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2-C3 olefin with an exocyclic methylene at C2 render PL analogues 47-49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47-49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.

Design, synthesis and evaluation of 2,2-dimethyl-1,3-dioxolane derivatives as human rhinovirus 3C protease inhibitors.

The human rhinovirus (HRV) is the most significant cause of the common cold all over the world. The maturation and replication of this virus entirely depend on the activity of a virus-encoded 3C protease. Due to the high conservation among different serotypes and the minimal homology existing between 3C protease and known mammalian enzymes, 3C protease has been regarded as an attractive target for the treatment of HRV infections. In this study, we identified a novel (4R,5R)-N4-(2-((3-methoxyphenyl)amino)ethyl)-2,2-dimethyl-N5-(naphthalen-2-yl)-1,3-dioxolane-4,5-dicarboxamide (7a) to be a HRV 3C protease inhibitor via virtual screening. Further research has been focused on the design, synthesis and in vitro biological evaluation of 7a derivatives. The studies revealed that compound 7d has an IC50 value of 2.50±0.7µM against HRV 3C protease, and it thus could serve as a promising compound for the development of novel anti-rhinoviral medicines.

Synthesis and evaluation of N-heteroaromatic ring-based analogs of piperlongumine as potent anticancer agents.

Piperlongumine (PL) selectively targets a wide spectrum of cancer cells and induces their death by triggering various pathways, including apoptosis, necrosis and autophagy. However, the poor solubility is a serious concern for intensive study and clinical application. We synthesized its analogs 1-9 by replacement of the trimethoxyphenyl of PL with an N-heteroaromatic ring and/or not introduction of 2-Cl. These compounds improved aqueous solubility and displayed potent anticancer activity. The most active compound 9 selectively enhanced ROS levels in colon cancer cells and inhibited the cell proliferation but sparing non-tumor colon cells. Importantly, 9 significantly repressed tumor growth in an HCT-116 xenograft mouse model, suggesting that these N-heteroaromatic ring-based analogs of PL warrant further investigation.

Identification of novel ROS inducer by merging the fragments of piperlongumine and dicoumarol.

A series of novel ROS inducers were designed by merging the fragments of piperlongumine and dicoumarol. Most of these derivatives showed potent in vitro activity against three cancer cell lines and good selectivity towards normal lung cells. The most potent and selective compound 3e was proven to exhibit obvious ROS elevation and excellent in vivo antitumor activity with suppressed tumor growth by 48.46% at the dose of 5mg/kg. Supported by these investigation, these findings encourage further investigation around this interesting antitumor chemotype.

Synthesis, structural characterization and biological evaluation of 4'-C-methyl- and phenyl-dioxolane pyrimidine and purine nucleosides.

Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and ß anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.

Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells.

Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1-58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1-58 yielded 3-35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7-C8 olefin of PL obtained 3-31/3-98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro-survival proteins, and inducing expression of pro-apoptotic proteins.

Horner-Wadsworth-Emmons approach to piperlongumine analogues with potent anti-cancer activity.

Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues.

Design, Synthesis and Pharmacological Evaluation of Novel Piperlongumine derivatives as Potential Antiplatelet Aggregation Candidate.

A series of novel piperlongumine derivatives (4a-i, 6a-i) were designed and synthesized. The inhibitory activities of platelet aggregation induced by ADP and AA in vitro have been evaluated by bron turbidimetry and liver microsomal incubated assay. The assay results show that compounds 4e and 6e exhibited remarkable potency to that of the positive control piplartine and aspirin.

Silver(I)-Catalyzed Regioselective Construction of Highly Substituted α-Naphthols and Its Application toward Expeditious Synthesis of Lignan Natural Products.

A novel route has been developed for regioselective synthesis of highly substituted α-naphthols, binaphthols, and anthracenol through silver(I) catalyzed C(sp(3))-H/C(sp)-H, C(sp(2))-H/C(sp)-H functionalization of ß-ketoesters and alkynes, respectively, in a single step using water as a solvent. This protocol exhibited broad substrate scope and paved the way for synthesis of anticancer arylnaphthalene lignan natural products such as diphyllin, taiwanin E, and justicidin A with excellent selectivity.

Synthesis and antiviral evaluation of 2-amino-6-carbamoylpurine dioxolane nucleoside derivatives and their phosphoramidates prodrugs.

The synthesis of 9-(ß-d-1,3-dioxolan-4-yl)2,6-diaminopurine nucleoside phosphoramidate prodrugs as well as various 2-amino-6-carbamoylpurine dioxolane derivatives and their phosphoramidates prodrugs is reported. Their ability to block HIV and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM and Vero cells was also assessed.

Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents.

In an effort to expand the structure-activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity.

Synthesis and structure-activity relationships of novel ecdysteroid dioxolanes as MDR modulators in cancer.

Ecdysteroids, molting hormones of insects, can exert several mild, non-hormonal bioactivities in mammals, including humans. In a previous study, we have found a significant effect of certain derivatives on the ABCB1 transporter mediated multi-drug resistance of a transfected murine leukemia cell line. In this paper, we present a structure-activity relationship study focused on the apolar dioxolane derivatives of 20-hydroxyecdysone. Semi-synthesis and bioactivity of a total of 32 ecdysteroids, including 20 new compounds, is presented, supplemented with their complete 1H- and 13C-NMR signal assignment.

1H and 13C NMR investigation of 20-hydroxyecdysone dioxolane derivatives, a novel group of MDR modulator agents.

The synthesis, structure elucidation and the complete (1)H and (13)C signal assignment of a series of dioxolane derivatives of 20-hydroxyecdysone, synthesized as novel modulators of multidrug resistance, are presented. The structures and NMR signal assignment were established by comprehensive one-dimensional and two-dimensional NMR spectroscopy supported by mass spectrometry.