Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents

Grigolo, Thiago A.; Braga, Carolyne B.; Ornelas, Cátia; Russowsky, Dennis; Ferreira-Silva, Guilherme Álvaro; Ionta, Marisa; Pilli, Ronaldo Aloise

doi:10.1016/j.bioorg.2021.105292

Cited by 4 publications

(6 citation statements)

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“…The preparation of the clickable derivative ( 12 , BCN-PPT) of the natural product piplartine ( 8 , PPT) is outlined in Scheme . 4-Hydroxypiplartine ( 9 , 4-HOPPT) was synthesized in five steps, according to methodologies previously described by our group. , We have chosen to modify the 4-hydroxy derivative of PPT because it enables the conjugation of linkers or other moieties to its structure in a simple and versatile way without compromising any essential residue for the PPT antitumor activity. The hydroxyl group in 9 was esterified to the carboxylic acid 10 in moderate yield (50%) through the opening of glutaric anhydride in the presence of catalytic amounts of DMAP in dichloromethane (DCM) under reflux.…”

Section: Resultsmentioning

confidence: 99%

Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics

et al. 2021

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This contribution describes the design and synthesis of multifunctional micelles based on amphiphilic brush block copolymers (BBCPs) for imaging and selective drug delivery of natural anticancer compounds. Well-defined BBCPs were synthesized via one-pot multi-step sequential grafting-through ring-opening metathesis polymerization (ROMP) of norbornene-based macroinitiators. The norbornenes employed contain a poly(ethylene glycol) methyl ether chain, an alkyl bromide chain, and/or a near-infrared (NIR) fluorescent cyanine dye. After block copolymerization, post-polymerization transformations using bromide−azide substitution, followed by the strain-promoted azide−alkyne cycloaddition (SPAAC) allowed for the functionalization of the BBCPs with the piplartine (PPT) moiety, a natural product with well-documented cytotoxicity against cancer cell lines, via an ester linker between the drug and the polymer side chain. The amphiphilic BBCPs self-assembled in aqueous media into nano-sized spherical micelles with neutral surface charges, as confirmed by dynamic light scattering analysis and transmission electron microscopy. During self-assembly, paclitaxel (PTX) could be effectively encapsulated into the hydrophobic core to form stable PTX-loaded micelles with high loading capacities and encapsulation efficiencies. The NIR fluorescent dye-containing micelles exhibited remarkable photophysical properties, excellent colloidal stability under physiological conditions, and a pH-induced disassembly under slightly acidic conditions, allowing for the release of the drug in a controlled manner. The in vitro studies demonstrated that the micelles without the drug (blank micelles) are biocompatible at concentrations of up to 1 mg mL −1 and present a high cellular internalization capacity toward MCF-7 cancer cells. The drug-functionalized micelles showed in vitro cytotoxicity comparable to free PPT and PTX against MCF-7 and PC3 cancer cells, confirming efficient drug release into the tumor environment upon cellular internalization. Furthermore, the drug-functionalized micelles exhibited higher selectivity than the pristine drugs and preferential cellular uptake in human cancer cell lines (MCF-7 and PC3) when compared to the normal breast cell line (MCF10A). This study provides an efficient strategy for the development of versatile polymeric nanosystems for drug delivery and image-guided diagnostics. Notably, the easy functionalization of BBCP side chains via SPAAC opens up the possibility for the preparation of a library of multifunctional systems containing other drugs or functionalities, such as target groups for recognition.

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Section: Resultsmentioning

confidence: 99%

Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics

et al. 2021

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“…[54] Overall, reduction of the hydroxyl group in the cinnamoyl moiety does not affect anticancer potency (Figure 5 (normal breast cancer) and PNT2 (normal prostate cancer) cells, in vitro. [57] Among all proposed derivatives, we have considered only IC 50 = 1.7 ± 0.1 and 1.6 ± 0.9 μM, which is higher than native PL. [57] Further, 12 and 22 cause apoptosis along with reduced G2/M and G0/G1 populations indicates a cell cycle arrest in the G2/M phase in oestrogen positive MCF-7.…”

Section: Anticancer Potency Of Proposed Pl-derivativesmentioning

confidence: 99%

“…[57] Among all proposed derivatives, we have considered only IC 50 = 1.7 ± 0.1 and 1.6 ± 0.9 μM, which is higher than native PL. [57] Further, 12 and 22 cause apoptosis along with reduced G2/M and G0/G1 populations indicates a cell cycle arrest in the G2/M phase in oestrogen positive MCF-7. From SAR, attachment of monastrol derivatives with 4-hydroxypiplartine via 1,2,3-triazole linker combinedly exhibited higher cytotoxicity than native PL (Figure 5: Scheme 7).…”

Section: Anticancer Potency Of Proposed Pl-derivativesmentioning

confidence: 99%

“…Then, selective derivatives were tested against MCF‐7, HeLa, Caco‐2 (colorectal adeno‐carcinoma) and PC3 (prostate adenocarcinoma), MCF10A (normal breast cancer) and PNT2 (normal prostate cancer) cells, in vitro. [ 57 ] Among all proposed derivatives, we have considered only 11 , 12 , 22 , 25 , 32 and 33 for present review as per eligibility criteria mentioned in PRISMA. Among six derivatives, 12 and 22 exhibited anticancer at >10 μM against all cell lines (Figure 5: Scheme 7).…”

Section: Anticancer Potency Of Proposed Pl‐derivativesmentioning

confidence: 99%

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

Swain,

Sahoo

2024

Archiv der Pharmazie

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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.

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“…1,2,3‐Triazole tethered monastrol‐piplartine/goniothalamin hybrids 131a,b (IC 50 : 1.6 and 3.5 µM, MTT assay) were not inferior to piplartine (IC 50 : 3.4 µM) and goniothalamin (IC 50 : 13.7 µM) against MCF‐7 breast cancer cells and displayed relatively low cytotoxicity (IC 50 : 9.0 and 55.6 µM) toward normal MCF‐10A breast cells. [ 171 ] Mechanistically, hybrid 131a induced cell‐cycle arrest at the G2/M phase and apoptosis in MCF‐7 cells. 6‐Methyluracil‐1,2,3‐triazole‐acridine hybrid 132 (IC 50 : 2.7 µM, MTT assay) was comparable to doxorubicin (IC 50 : 2.06 µM) against MCF‐7 breast cancer cells and showed potent inhibitory activity against MCF‐7 topoisomerase IIB with IC 50 value of 520 nM.…”

Section: 23‐triazole Acted As a Linkermentioning

confidence: 99%

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

Song,

Zhang,

Zhang

et al. 2023

Archiv der Pharmazie

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Breast cancer, as one of the most common invasive malignancies and the leading cause of cancer‐related deaths in women globally, poses a significant challenge in the world health system. Substantial advances in diagnosis and treatment have significantly improved the survival rate of breast cancer patients, but the number of incidences and deaths of breast cancer are projected to increase by 40% and 50%, respectively, by 2040. Chemotherapy is one of the principal treatments for breast cancer therapy, but multidrug resistance and severe side effects remain the major obstacles to the success of treatment. Hence, there is a vital need to develop novel chemotherapeutic agents to combat this deadly disease. 1,2,3‐Triazole, which can be effectively constructed by click chemistry, not only can serve as a linker to connect different anti‐breast cancer pharmacophores but also is a valuable pharmacophore with anti‐breast cancer potential and favorable properties such as hydrogen bonding, moderate dipole moment, and enhanced water solubility. Particularly, 1,2,3‐triazole‐containing hybrids have demonstrated promising in vitro and in vivo anti‐breast cancer potential against both drug‐sensitive and drug‐resistant forms and possessed excellent selectivity by targeting different biological pathways associated with breast cancer, representing privileged scaffolds for the discovery of novel anti‐breast cancer candidates. This review concentrates on the latest advancements of 1,2,3‐triazole‐containing hybrids with anti‐breast cancer potential, including work published between 2020 and the present. The structure–activity relationships (SARs) and mechanisms of action are also reviewed to shed light on the development of more effective and multitargeted candidates.

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Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents

Cited by 4 publications

References 63 publications

Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics

Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics

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

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

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