Design, Synthesis, and Cytotoxicity of Perbutyrylated Glycosides of 4β-Triazolopodophyllotoxin Derivatives

Zi, Cheng-Ting; Liu, Zhenhua; Li, Gen-Tao; Li, Yan; Zhou, Jun; Zhang, Ding; Hu, Jiang‐Miao; Jiang, Zi‐Hua

doi:10.3390/molecules20023255

Cited by 15 publications

(8 citation statements)

References 36 publications

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“…This observation agrees with our earlier reports that several podophyllotoxin glycoconjugates containing perbutyrylated sugar residues show higher anticancer activity than those without butyryl groups. 16 , 17 In comparison to 29 , the 4′-demethylated analog 32 loses its activity, confirming the earlier observation that the substitution group on the 4′-position of podophyllotoxin scaffold can significantly affect the anticancer potency of podophyllotoxin derivatives. 29 Previously, we reported several groups of monomeric podophyllotoxin derivatives bearing similar structure elements as those dimeric ones in the present study.…”

Section: Resultssupporting

confidence: 82%

“… 29 Previously, we reported several groups of monomeric podophyllotoxin derivatives bearing similar structure elements as those dimeric ones in the present study. 16 , 17 , 29 Some of those monomeric derivatives show good anticancer activity with IC 50 values in low μM range. Since most of the dimeric podophyllotoxin derivatives in this study display weak anticancer activity, dimerization might not be a good strategy for improving the potency of podophyllotoxin derivatives.…”

Section: Resultsmentioning

confidence: 99%

“… 16 – 18 Our studies showed that podophyllotoxin derivatives with a perbutyrylated sugar residue displayed higher activity than their counterparts lacking butyryl groups. 16 , 17 There have also been reports on the synthesis of dimeric podophyllotoxin derivatives 19 , 20 which exhibited promising in vitro anticancer activity against different human tumour cell lines. In the present study, a group of dimeric podophyllotoxin derivatives 4 ( Figure 1 ), with different linkers have been prepared using the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and anticancer activity of dimeric podophyllotoxin derivatives

Zi¹,

Liu²,

Xu³

et al. 2018

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BackgroundPodophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of antitumor drugs. Several podophyllotoxin-derived antitumor agents, including etoposide, are currently in clinical use; however, their therapeutic efficacy is often limited due to side effects and the development of resistance by cancer cells. Previous studies have shown that 4β-1,2,3-triazole derivatives of podophyllotoxin exhibit more potent anticancer activity and better binding to topoisomerase-II than etoposide. The effect of dimerization of such derivatives on the anticancer activity has not been studied.MethodsTwo moieties of podophyllotoxin were linked at the C-4 position via 1,2,3-triazole rings to give a series of novel dimeric podophyllotoxin derivatives. 4β-Azido-substituted podophyllotoxin derivatives (23 and 24) were coupled with various dipropargyl functionalized linkers by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to provide dimeric products in very good yield. The in vitro anticancer activity of the synthesized compounds was evaluated by MTT assay against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). The normal BEAS-2B (lung) cell line was also included for study in order to evaluate the cancer selectivity of the most active compound as compared with normal cells.ResultsA group of 16 dimeric podophyllotoxin derivatives with different linkers were synthesized and structurally characterized. Most compounds do not show significant cytotoxicity (IC50 > 40 mM) against all five cancer cell lines. However, one compound (29) which bears a perbutyrylated glucose residue on the glycerol linker is highly potent against all five cancer cell lines tested, with IC50 values ranging from 0.43 to 3.50 μM. This compound (29) also shows good selectivity towards cancer cell lines as compared with the normal BEAS-2B (lung) cell line, showing selectivity indexes from 4.4 to 35.7.ConclusionThe anticancer activity of dimeric podophyllotoxin derivatives is generally speaking not improved as compared to their monomeric counterparts, and the potency of these dimeric derivatives can be largely affected by the nature of the linker between the two moieties. Among the synthesized derivatives, compound 29 is significantly more cytotoxic and selective towards cancer cells than etoposide and cisplatin, which are currently in clinical use. Compound 29 is a promising anticancer drug and needs further studies.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and anticancer activity of dimeric podophyllotoxin derivatives

Zi¹,

Liu²,

Xu³

et al. 2018

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“…The key intermediate ( 3 ) was obtained as shown in Scheme 1 . In the presence of potassium carbonate, treatment of mollugin ( 1 ) with 3-bromoprop-1-yne ( 2 ) in anhydrous DMF yielded the O -propargylated mollugin ( 3 ) in 85% yield [ 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Antitumor Activity of 1-Substituted 1,2,3-Triazole-Mollugin Derivatives

Luo

Zhang

et al. 2021

Molecules

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A new series of mollugin-1,2,3-triazole derivatives were synthesized using a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated mollugin with aryl azides. All the compounds were evaluated for their cytotoxicity on five human cancer cell lines (HL-60, A549, SMMC-7721, SW480, and MCF-7) using MTS assays. Among the synthesized series, most of them showed cytotoxicity and most of all, compounds 14 and 17 exhibited significant cytotoxicity of all five cancer cell lines.

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“…Investigation of the structure-activity relationships of PPT indicates that the trans-lactone, the 4β-substituted moiety, and the 4′-demethyl moieties are essential for TOP-II inhibitory activity [9,10]. In recent years, our group and others have found that several analogs with N -substitutions at the C4 position show an improved antitumor activity compared with VP-16 [11,12,13,14,15,16,17,18,19,20,21,22,23]. In this study, furfuran amines of 4β -N -substituted podophyllotoxin derivatives were designed and synthesized.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of New Podophyllotoxin Derivatives with in Vitro Anticancer Activity

et al. 2015

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A series of novel podophyllotoxin derivatives were designed and synthesized. The cytotoxic activities of these compounds were tested against three tumor cell lines (HeLa, K562, and K562/A02). Most of the derivatives (IC50 = 1-20 μM) were found to have stronger cell growth inhibitory activity than positive control etoposide. Among them, 4β-N-[(E)-(5-((4-(4-nitrophenyl)-piperazin-1-yl)methyl)furan-2-yl)prop-2-en-1-amine]-4-desoxy-podophyllotoxin (9l) demonstrated significant inhibitory activity against HeLa, K562, and K562/A02 cell lines with IC50 values of 7. 93, 6.42, 6.89 μM, respectively.

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Design, Synthesis, and Cytotoxicity of Perbutyrylated Glycosides of 4β-Triazolopodophyllotoxin Derivatives

Cited by 15 publications

References 36 publications

Synthesis and anticancer activity of dimeric podophyllotoxin derivatives

Synthesis and anticancer activity of dimeric podophyllotoxin derivatives

Synthesis and Antitumor Activity of 1-Substituted 1,2,3-Triazole-Mollugin Derivatives

Synthesis and Evaluation of New Podophyllotoxin Derivatives with in Vitro Anticancer Activity

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