Design and synthesis of alepterolic acid and 5-fluorouracil conjugates as potential anticancer agents

Jin, Xin; Yang, Tingting; Xia, Chenlu; Wang, Nina; Li, Zi; Cao, Ji; Ma, Liang; Huang, Guozheng

doi:10.1016/j.mencom.2022.05.024

Cited by 4 publications

(3 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 20 ] As a frontline chemotherapeutic agent, FU is used in various treatment regimens for breast cancer when co‐administered with other anticancer drugs. [ 21 , 22 ] NAMPT is the rate‐limiting enzyme in nicotinamide adenine dinucleotide (NAD + ) biosynthesis and is a promising antitumor target. [ 23 ] FU has been reported to exert synergistic effects with the NAMPT inhibitor FK866, which increases the chemosensitivity of cancer cells to FU by inhibiting cell proliferation and inducing apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy

He,

Fang,

Zhu

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer‐PROTAC conjugation approach is developed to enhance tumor targeting and antitumor potency. Specifically, a smart prodrug is designed by conjugating “drugtamer” to a nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using a tumor microenvironment responsible linker. The “drugtamer” consists of fluorouridine nucleotide and DNA‐like oligomer. Compared to NAMPT PROTAC and the combination of PROTAC + fluorouracil, the designed prodrug AS‐2F‐NP demonstrates superior tumor targeting, efficient cellular uptake, improved in vivo potency and reduced side effects. This study provides a promising strategy for the precise delivery of PROTAC and synergistic antitumor agents.

show abstract

Section: Resultsmentioning

confidence: 99%

Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy

He,

Fang,

Zhu

et al. 2024

Advanced Science

View full text Add to dashboard Cite

show abstract

“…In our previous work of alepterolic acid modification, it was found that incorporation of different amine moieties to alepterolic acid, such as primary aliphatic amine, aromatic amine, piperidine, piperazine, etc., resulted in the improved activities against cancer cells [19–21] . Also, conjugates of alepterolic acid with 5‐fluorouracil derivatives showed increased anti‐cancer activities.…”

Section: Introductionmentioning

confidence: 97%

“…[18] In our previous work of alepterolic acid modification, it was found that incorporation of different amine moieties to alepterolic acid, such as primary aliphatic amine, aromatic amine, piperidine, piperazine, etc., resulted in the improved activities against cancer cells. [19][20][21] Also, conjugates of alepterolic acid with 5fluorouracil derivatives showed increased anti-cancer activities. A growing wealth of literature reflects that piperazine skeleton has been widely employed in the structural modification of natural products with poten-Supporting information for this article is available on the WWW under https://doi.org/10.1002/cbdv.202300208 Part of a Special Collection on In Honor of Professor Yue-Wei Guo.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Piperazine‐Tethered Derivatives of Alepterolic Acid as Anticancer Agents

Xia

Wang

et al. 2023

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

Alepterolic acid is a natural diterpenoid isolated from Aleuritopteris argentea with potential anti‐cancer activity. In this study, alepterolic acid was modified to construct a series of arylformyl piperazinyl derivatives (3a–3p). The synthesized derivatives were fully characterized with HRMS, NMR, and IR. Four compounds with inhibition rate higher than 30 % at 10 μM (3f, 3n, 3g and 3k) were further measured to obtain the IC50 values against four cancer cell lines, including hepatoma cell lines HepG2, lung cancer cell lines A549, estrogen receptor‐positive cell lines MCF7, and triple‐negative breast cancer (TNBC) cell lines MDA‐MB‐231 by MTT assay. It was found that these compounds were more effective to HepG2 and MDA‐MB‐231 cells, while less toxic to A549 and MCF7 cells, and compound 3n as the most toxic derivatve against MDA‐MB‐231 cell lines, with IC50 value of 5.55±0.56 μM. Trypan blue staining and colony formation assay showed that compound 3n inhibited the growth of MDA‐MB‐231 cells and prevented colony formation. Hoechst staining, flow cytometry and western blot analysis revealed that compound 3n induced caspase‐dependent apoptosis in MDA‐MB‐231 cells. Conclusively, compound 3n was demonstrated to be a potential anti‐cancer lead compound for further investigation.

show abstract

Benzylpiperazinyl Derivatives of Alepterolic Acid: Synthesis and Cytotoxic Evaluation

Wang,

Qin,

et al. 2024

Chemistry & Biodiversity

View full text Add to dashboard Cite

Natural products play a significant role in the development of modern drugs. Alepterolic acid, a labdane‐type diterpenoid firstly isolated from Aleuritopteris argentea (Gmél.) Fée, has been identified as a valuable template for the synthesis of potent anticancer agents by structural modification. In this study, a series of new derivatives was obtained by coupling alepterolic acid with benzylpiperazines. It was found that (3,4‐dichlorobenzyl)piperazinyl alepterolic acid (compound 6p) displayed the most toxic against MCF‐7 cell line, with IC50 value of 8.31±0.67 μM. Further investigations demonstrated that compound 6p induced morphological changes in MCF‐7 cells, inhibited proliferation in a time‐ and dose‐dependent manner. Furthermore, western blot analysis revealed that compound 6p induced a significant increase in cleaved caspase‐9, cleaved caspase‐3, cleaved poly (ADP‐ribose) polymerase (PARP) and Bax/Bcl2 ratio in MCF‐7 cells. All of these results confirmed that compound 6p induced endogenous apoptosis in MCF‐7 cells. Conclusively, the findings suggest that the incorporation of benzylpiperazine to alepterolic acid represents a promising approach for the discovery of new drug candidates.

show abstract

Design and synthesis of alepterolic acid and 5-fluorouracil conjugates as potential anticancer agents

Cited by 4 publications

References 14 publications

Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy

Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy

Synthesis and Evaluation of Piperazine‐Tethered Derivatives of Alepterolic Acid as Anticancer Agents

Benzylpiperazinyl Derivatives of Alepterolic Acid: Synthesis and Cytotoxic Evaluation

Contact Info

Product

Resources

About