Podophyllotoxin–pterostilbene fused conjugates as potential multifunctional antineoplastic agents against human uveal melanoma cells

Zhang, Lei; Wang, Jing; Liu, Lai; Zheng, Chengyue; Wang, Yang; Chen, Yongzheng; Wei, Gang

doi:10.1039/c6ra28832d

Cited by 10 publications

(5 citation statements)

References 42 publications

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“…To create more effective antitumor candidates that more affordable, hybridization of natural products or natural product-drug is one promising approach for designing lead compounds [ 27 , 28 ]. Recently, our group has described the synthesis and antiproliferative potential of the PPT conjugates [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ], and some derivatives showed dramatic activity. For example, the artesunate-podophyllotoxin conjugate exhibited notable cytotoxicity against several cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells

et al. 2017

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With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, P-A, exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC50 values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, P-A efficiently triggered cell cycle arrest and induced apoptosis in MKN-45 and BGC-823 cells due to modulation of cell cycle arrest- (CDK1, CDK2, CyclinA and CyclinB1) and apoptosis- (cleaved caspase-3, -8 and -9) related proteins, respectively. Further mechanism studies revealed that P-A could increase the expression levels of RARα and RARβ, and decrease the level of RARγ in MKN-45 and BGC-823 cells. Finally, P-A inhibited the ERK1/2 and AKT signaling in the above two cancer cell lines. More importantly, the underlying mechanisms of P-A were similar to those of precursor PPT but different with the other precursor ATRA. Together, the conjugate P-A was a promising candidate for the potential treatment of human gastric cancer.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells

et al. 2017

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“…Furthermore, conjugate 12a showed great potential in inhibiting migration and metastasis of MuM-2B cells by increasing E-cadherin levels and downregulating the levels of vascular endothelial growth factor receptor 2 (VEGFR-2) and matrix metalloproteinase-2 (MMP-2) in these cells. Reductions in the expression levels of Topo IIα and Topo IIβ enzymes were also observed [ 42 ].…”

Section: C-ring Modifications Of the Podophyllotoxin Skeletonmentioning

confidence: 99%

“…Pterostilbene is a natural demethylated analogue of resveratrol originally isolated from the heartwood of sandalwood with potential health benefits in inflammatory dermatoses, photoprotection, antioxidant activity, insulin sensitivity, blood glycemia and lipid levels, cardiovascular diseases, aging, memory, and cognition; it also exerts effects in cancer prevention and therapy in a wide range of tumors [39][40][41]. Pterostilbene was used by Zhang's group to synthesize novel podophyllotoxin-pterostilbene hybrids (12) [42]. Conjugate 12a (Figure 5) showed a better anticancer effect against uveal melanoma cells (MuM-2B cells) than pterostilbene (IC 50 = 0.08 µM and 40 µM, respectively) but less cytotoxicity against human umbilical vein endothelial cells (HUVEC cells) than podophyllotoxin (IC 50 = 0.36 µM and 0.01 µM, respectively), which indicates that this hybrid had less toxicity than the parent compound.…”

Section: Podophyllotoxin Hybrids Synthesized Through a Haloacyl Inter...mentioning

confidence: 99%

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Miranda-Vera,

Hernández,

García-García

et al. 2023

Pharmaceutics

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Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

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“…Depending on the chosen modern molecule hybridization strategy [ 15 , 16 ], podophyllotoxin/epipodophyllotoxin can hybridize with amino acid/peptide [ 17 , 18 ], azole [ 19 ], biotin [ 20 ], carbamate [ 21 ], chalcone [ 22 ], cinnamic acid [ 23 ], cinnamic acid [ 24 ], ferrocene [ 25 ], furan/pyrrole [ 26 ], hydroxamic acid [ 27 ], indole [ 28 ], norcantharidin [ 29 ], pyridine/pyrimidine [ 30 ], pterostilbene [ 31 ], retinoic acid [ 32 ], sugar [ 33 ], (thio)urea [ 34 ], or sulfur [ 35 ] ( Figure 1 ). These have been subjected to extensive research and have been shown to be highly active against both MDR and drug-sensitive cancer cell lines with IC 50 or GI 50 values at a nanomolar level; however, the water solubility, bioactivities, and toxicity still need to be improved.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

et al. 2021

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Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-N-sulfonyl amidine hybrids (4a–4v, 5a–5f) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF3 group performed best (IC50: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC50 values.

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Podophyllotoxin–pterostilbene fused conjugates as potential multifunctional antineoplastic agents against human uveal melanoma cells

Abstract: Conjugate B1 showed potential multifunctional antineoplastic activity against human uveal melanoma cells.

Cited by 10 publications

References 42 publications

Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells

Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

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