Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates

Petrov, Rostislav A.; Maklakova, Svetlana Yu.; Ivanenkov, Yan A.; Petrov, Stanislav A.; Sergeeva, Olga V.; Yamansarov, Emil Yu.; Saltykova, Irina V.; Kireev, Igor I.; Alieva, Irina B.; Deyneka, Ekaterina V.; Sofronova, Alina A.; Aladinskaia, Anastasiia V.; Trofimenko, Alexandre V.; Yamidanov, R. S.; Ковалев, С. В.; Kotelianski, Victor; Zatsepin, Timofei S.; Белоглазкина, Е. К.; Majouga, Alexander G.

doi:10.1016/j.bmcl.2017.12.032

Cited by 19 publications

(25 citation statements)

References 36 publications

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“…Previously investigated conjugates of PTX were linked to ASGPR ligands A, B, and C by an ester bond at the 2′-position of the terpene carbon skeleton. 20 These compounds subsequently showed activity comparable to the parent drug. Because the hydroxyl group in the C2′-position of DTX is the most reactive, similarly to the C2′−OH of PTX, 22 we synthesized glycoconjugates 3−7 via the same synthetic route (Schemes 1−3).…”

Section: ■ Design and Synthesismentioning

confidence: 99%

“…Further, compounds 1 and 2 were conjugated with GalNAc derivatives A, B, and C as the ASGPR ligands (Figure 1), which were previously synthesized. 20 The azide−alkyne Huisgen (CuAAC) reactions were performed in the presence of Cu(I) and the base (Schemes 2 and 3). were isolated by column chromatography.…”

Section: ■ Design and Synthesismentioning

confidence: 99%

“…19 We recently obtained and studied covalent drug delivery systems based on paclitaxel (PTX) and doxorubicin. 20,21 The developed conjugates showed a high potential against HCC due to excellent ASGPR binding affinity and cytotoxicity against HepG2 cells, retained a mechanism of action against cancerous cells similar to the unmodified drugs, and exhibited good accumulation in HCC cells. The next-generation taxane agent DTX has a higher level of cytotoxic activity against HCC cells.…”

Section: ■ Introductionmentioning

confidence: 99%

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New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

et al. 2020

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In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21–75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20–35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.

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Section: ■ Design and Synthesismentioning

confidence: 99%

Section: ■ Design and Synthesismentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

et al. 2020

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“…Accurate prediction of DTIs can also substantially accelerate lead generation. Drug-target interaction prediction can be also regarded as a useful step in biomedical research and precision medicine [1][2][3][4][5][6][7][8][9]. However, it is still time consuming for traditional experimental approaches to identify potential DTIs, and the success rates are also very low.…”

Section: Introductionmentioning

confidence: 99%

Drug-Target Interaction Prediction via Dual Laplacian Graph Regularized Logistic Matrix Factorization

Wang

2021

BioMed Research International

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Drug-target interactions provide useful information for biomedical drug discovery as well as drug development. However, it is costly and time consuming to find drug-target interactions by experimental methods. As a result, developing computational approaches for this task is necessary and has practical significance. In this study, we establish a novel dual Laplacian graph regularized logistic matrix factorization model for drug-target interaction prediction, referred to as DLGrLMF briefly. Specifically, DLGrLMF regards the task of drug-target interaction prediction as a weighted logistic matrix factorization problem, in which the experimentally validated interactions are allocated with larger weights. Meanwhile, by considering that drugs with similar chemical structure should have interactions with similar targets and targets with similar genomic sequence similarity should in turn have interactions with similar drugs, the drug pairwise chemical structure similarities as well as the target pairwise genomic sequence similarities are fully exploited to serve the matrix factorization problem by using a dual Laplacian graph regularization term. In addition, we design a gradient descent algorithm to solve the resultant optimization problem. Finally, the efficacy of DLGrLMF is validated on various benchmark datasets and the experimental results demonstrate that DLGrLMF performs better than other state-of-the-art methods. Case studies are also conducted to validate that DLGrLMF can successfully predict most of the experimental validated drug-target interactions.

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“…Due to the presence of 3-OH group this derivative can be esterified and used for target delivery to cancer cells via prodrug-type conjugates. 20,21 N-methylpiperazinylamide 5 also demonstrated high values of cytotoxicity, although appeared slightly less active in compare with 4.…”

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confidence: 96%

Synthesis and Сytotoxicity of A-Azepanobetulinic AcidN-Methyl-Piperazinylamide

Giniyatullina

Казакова

Байкова

et al. 2019

Natural Product Communications

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Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates

Cited by 19 publications

References 36 publications

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

Drug-Target Interaction Prediction via Dual Laplacian Graph Regularized Logistic Matrix Factorization

Synthesis and Сytotoxicity of A-Azepanobetulinic AcidN-Methyl-Piperazinylamide

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