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1.
Med Chem ; 18(1): 130-139, 2022.
Article in English | MEDLINE | ID: mdl-33222676

ABSTRACT

BACKGROUND: Podophyllotoxin is a natural lignan which possesses anticancer and antiviral activities. Etoposide and teniposide are semisynthetic glycoside derivatives of podophyllotoxin and are increasingly used in cancer medicine. OBJECTIVE: The present work aimed to design and synthesize a series of 2, 4, 5-trideoxyhexopyranosides derivatives of 4'-demethylepipodophyllotoxin as novel anticancer agents. METHODS: A divergent de novo synthesis of 2, 4, 5-trideoxyhexopyranosides derivatives of 4'- demethylepipodophyllotoxin has been established via palladium-catalyzed glycosylation. The abilities of synthesized glycosides to inhibit the growth of A549, HepG2, SH-SY5Y, KB/VCR and HeLa cancer cells were investigated by MTT assay. Flow cytometric analysis of cell cycle with propidium iodide DNA staining was employed to observe the effect of compound 5b on cancer cell cycle. RESULTS: Twelve D and L monosaccharide derivatives 5a-5l have been efficiently synthesized in three steps from various pyranone building blocks employing de novo glycosylation strategy. Dmonosaccharide 5b showed the highest cytotoxicity on five cancer cell lines with the IC50 values ranging from 0.9 to 6.7 µM. It caused HepG2 cycle arrest at G2/M phase in a concentrationdependent manner. CONCLUSION: The present work leads to the development of novel 2, 4, 5-trideoxyhexopyranosides derivatives of 4'-demethylepipodophyllotoxin. The biological results suggest that the replacement of the glucosyl moiety of etoposide with 2, 4, 5-trideoxyhexopyranosyl is favorable to their cytotoxicity. D-monosaccharide 5b was observed to cause HepG2 cycle arrest at the G2/M phase in a concentration- dependent manner.


Subject(s)
Antineoplastic Agents , Podophyllotoxin , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , HeLa Cells , Humans , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/pharmacology , Structure-Activity Relationship
2.
Eur J Pharmacol ; 905: 174189, 2021 Aug 15.
Article in English | MEDLINE | ID: mdl-34033816

ABSTRACT

Heterocycle modification has been widely and successfully employed in the antitumor drugs. However, the different antitumor efficacy was corelated with the heterocycle substituted, and the genetic mechanism underlying these effects has not been elucidated. In this study, the intrinsic regularity between different types of heterocycle-substituted DMEP derivative compounds and the mechanisms of their antitumor activity was preliminarily disclosed. Triazole/thiadiazole substituted 4'-demethylepipodophyllotoxin derivatives induced more severe DNA damage and higher levels of 26S proteasomal Topo IIß degradation, though inhibited the recruition of γH2AX to resist the DNA damage. The reduced DNA repair led to higher up-regulation of cell cycle arrest proteins, and ultimately DNA damage mediated-ATM/ATR apoptotic pathways and specifically activated DNA damage response gene TMEM133, which induced apoptosis through up-regulation of G2/M cell cycle arrest-related genes. Over-expression and knock-out of TMEM133 demonstrated that TMEM133 is essential for inhibition of the tumor cell growth during treatment with triazole/thiadiazole substituted 4'-demethylepipodophyllotoxin derivatives.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Podophyllotoxin/analogs & derivatives , Thiadiazoles/chemistry , Triazoles/chemistry , Animals , Apoptosis/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Cell Cycle Checkpoints/drug effects , DNA Damage/drug effects , DNA Repair/drug effects , DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , Etoposide/pharmacology , Female , Gene Expression Regulation/drug effects , Gene Knockout Techniques , HeLa Cells , Histones/metabolism , Humans , Male , Mice, Inbred C57BL , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacology , Up-Regulation/drug effects
3.
Zhongguo Zhong Yao Za Zhi ; 44(22): 4874-4879, 2019 Nov.
Article in Chinese | MEDLINE | ID: mdl-31872595

ABSTRACT

According to drug design flattening principle and using podophyllotoxin or 4'-demethylepipodophyllotoxin and aldehydes as starting material,a series of podophyllotoxin derivatives containing an imine structure with low toxicity were highly effective synthesized. Nine target compounds were successfully synthesized,and their structures were confirmed by ~1H-NMR,HR-ESI-MS and melting point data analysis. Using etoposide as positive control drug,nine target compounds were screened for cytotoxicity against He La cells in vitro by MTT method. The antitumor activity screening results showed that compound 6 b,6 d,6 e,6 f,6 g,6 i exhibited higher inhibitory rate against He La cells than those of control drug VP-16. It provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Podophyllotoxin/pharmacology , Drug Design , Structure-Activity Relationship
4.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-1008176

ABSTRACT

According to drug design flattening principle and using podophyllotoxin or 4'-demethylepipodophyllotoxin and aldehydes as starting material,a series of podophyllotoxin derivatives containing an imine structure with low toxicity were highly effective synthesized. Nine target compounds were successfully synthesized,and their structures were confirmed by ~1H-NMR,HR-ESI-MS and melting point data analysis. Using etoposide as positive control drug,nine target compounds were screened for cytotoxicity against He La cells in vitro by MTT method. The antitumor activity screening results showed that compound 6 b,6 d,6 e,6 f,6 g,6 i exhibited higher inhibitory rate against He La cells than those of control drug VP-16. It provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Podophyllotoxin/pharmacology , Structure-Activity Relationship
5.
Eur J Med Chem ; 158: 951-964, 2018 Oct 05.
Article in English | MEDLINE | ID: mdl-30265994

ABSTRACT

4'-Demethylepipodophyllotoxin (DMEP) derivatives are broad-spectrum and potent antitumor leading compound. Because of their unacceptable toxicity, DMEP derivatives often failed in the development of new drug. Until now, there was no report on the millimolar-potency toxicity of DMEP derivatives by modifying the molecule structure of DMEP. For the first time, this work discovered leading compounds with millimolar-potency toxicity by modifying the molecule structure of DMEP. The IC50 value of 4ß-S-(5-fluorobenzoxazole-2-)-4-deoxy-4'-demethylepipodophyllotoxin (Compound 2) was around 323.4-2000.9 µM on human healthy cells (i.e., HL-7702, H8, MRC-5 and HMEC), which was significantly reduced by 171-1999 times than podophyllotoxin (1.0-2.6 µM) and 9-80 times than etoposide (21.5-75.4 µM). Compared with the treatment of etoposide, DNA repair proteins HMGB1 and PARK7 were specifically activated and the expression of anti-apoptotic proteins were up-regulated in HL-7702 cells after the treatment of Compound 2. These indicated the toxicity of Compound 2 was synergistically reduced by DNA repair and anti-apoptosis pathway.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Podophyllotoxin/analogs & derivatives , Apoptosis/drug effects , Cell Line , Cell Line, Tumor , Halogenation , Hep G2 Cells , Humans , Models, Molecular , Neoplasms/drug therapy , Neoplasms/metabolism , Oxazoles/chemistry , Oxazoles/pharmacology , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacology
6.
Zhongguo Zhong Yao Za Zhi ; 42(12): 2323-2328, 2017 Jun.
Article in Chinese | MEDLINE | ID: mdl-28822187

ABSTRACT

The glycosides of 4'-demethylepipodophyllotoxin (DMEP) possess various pharmacological activities; however, the chemical synthesis of these glycosides faces challenges in regioselectivity, stereoselectivity, and the protection and de-protection of functional groups. In this work, a novel glycosyltransferase (GT) gene AbGT5 from Aloe barbadensis was successfully cloned, heterogeneously expressed and purified. Recombinant AbGT5 was able to catalyze the glycosylation of DMEP and the glycosylated product, which was separated from the preparative scale reaction, was characterized as DMEP 4'-O-ß-D-glucoside via MS, 1H-NMR, 13C-NMR, HSQC and HMBC. According to the investigations of enzyme properties, AbGT5 show the highest activity around 20 ℃ in the buffer of pH 9.0, and it was independent of divalent metal ions. Under the optimum conditions, the conversion rate of DMEP can reach 80%. Above all, in this work the enzymatic glycosylation of DMEP was achieved with high efficiency by the novel GT AbGT5.


Subject(s)
Glucosides/chemistry , Glycosides/chemistry , Glycosyltransferases/metabolism , Podophyllotoxin/analogs & derivatives , Aloe/enzymology , Aloe/genetics , Glycosylation , Glycosyltransferases/genetics , Podophyllotoxin/chemistry
7.
Drug Evaluation Research ; (6): 28-36, 2017.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-515036

ABSTRACT

Objective To study the inhibitory effect on proliferation of Hela cells of podophyllotoxin,4'-demethylepi-podophyllotoxin and drug combination of different proportion of nano-sillca (SiO2) and 4'-demethylepi-podophyllotoxin in vitro,and discuss the mechanism.Methods Used ethyl silicate hydrolysis method to prepare 25 nm SiO2 sample,next carried 4'-demethylepi-podophyllotoxin after the surface modification,and measure cell campatibility by MTT method and Hoechst 33342.The inhibitory effect of podophyllotoxin,4'-demethylepi-podophyllotoxin and drug combination on proliferation of Hela cells was measured by MTT assay.Hoechst 33342 staining method was used to detect cell apoptosis.The effect ofdmg combination treatment on cell morphology was observed by inverted microscope.Western blotting technique was used to detected effect of 4'-demethylepi-podophyllotoxin and drug combination on expression of apoptosis related protein.Results Inhibitory effect onproliferation of Hela cells of 4'-demethylepi-podophyllotoxin is superior to podophyllotoxin,inhibitory effect of drug combination is superior to the single 4'-demethylepi-podophyllotoxin,the inhibition of drug combination with 0.125 μg/mL nano SiO2 and 6.25 μg/mL 4'-demethylepi-podophyllotoxin is the most obvious.MTT and Hoechst 33342 experimental results showed that the 25 nm SiO2 have good cell compatibility.Podophyllotoxin,4'-demethylepi-podophyllotoxin and drug combination can induce apoptosis.Western blotting results showed that 4'-demethylepi-podophyllotoxin and drug combination can up-regulate the ratio of Bax/Bcl-2 and the expression level of Caspase-3、P53 and P38.Conclusion In vitro experimental performance of drug combination is superior to single 4'-demethylepi-podophyllotoxin,it is may by effecting the expression of Bcl-2,Bax,Caspase-3,P53,and P38 and others apoptosis related protein to induce Hela cell apoptosis.

8.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-275130

ABSTRACT

The glycosides of 4'-demethylepipodophyllotoxin (DMEP) possess various pharmacological activities; however, the chemical synthesis of these glycosides faces challenges in regioselectivity, stereoselectivity, and the protection and de-protection of functional groups. In this work, a novel glycosyltransferase (GT) gene AbGT5 from Aloe barbadensis was successfully cloned, heterogeneously expressed and purified. Recombinant AbGT5 was able to catalyze the glycosylation of DMEP and the glycosylated product, which was separated from the preparative scale reaction, was characterized as DMEP 4'-O-β-D-glucoside via MS, 1H-NMR, 13C-NMR, HSQC and HMBC. According to the investigations of enzyme properties, AbGT5 show the highest activity around 20 ℃ in the buffer of pH 9.0, and it was independent of divalent metal ions. Under the optimum conditions, the conversion rate of DMEP can reach 80%. Above all, in this work the enzymatic glycosylation of DMEP was achieved with high efficiency by the novel GT AbGT5.

9.
J Control Release ; 241: 81-93, 2016 11 10.
Article in English | MEDLINE | ID: mdl-27639682

ABSTRACT

In this work, two tertiary amine-derived 4'-demethylepipodophyllotoxin (DMEP) conjugates (DC and DP) have been designed and synthesized using N,N,N'-trimethyl-N'-(4-carboxyl benzyl)-1,3-propanediamine (CPDM) and 4-(4-methylpiperazinomethyl)benzoic acid (PBA) as the targeting ligands. Both DC and DP exhibited strong in vitro cytotoxicity against small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Cellular uptake efficiencies of DC and DP in human alveolar type II epithelial cells were significantly enhanced compared to DMEP and etoposide (VP-16), which were demonstrated to be concentration-, time- and energy-dependent. The active transport process of DC and DP might be mediated by organic cation transporters (OCTs). After systemic administration in mice, both DC and DP selectively accumulated in the lung, displaying the highest Cmax and AUC0-t values of all tested tissues. Compared with DMEP and VP-16, DC and DP remarkably reduced the lung weight and the number of lung metastases of B16 melanoma in mice, and further prolonged the survival of tumor-bearing mice. Also, DC and DP exhibited comparable levels of cell cycle arrest and cell apoptosis. Furthermore, DC and DP demonstrated minimum toxicity towards vital organs and reduced gastrointestinal injury compared to DMEP and VP-16. Taken together, tertiary amine-derived moieties such as CPDM and PBA represent an efficient yet safe strategy to achieve lung-targeted drug delivery.


Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Benzoates/chemistry , Lung Neoplasms/drug therapy , Podophyllotoxin/analogs & derivatives , Propylamines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Inbred Strains , Molecular Structure , Molecular Targeted Therapy , Piperazines/chemistry , Podophyllotoxin/chemical synthesis , Podophyllotoxin/chemistry , Podophyllotoxin/therapeutic use , Structure-Activity Relationship , Tissue Distribution , Xenograft Model Antitumor Assays
10.
Bioorg Med Chem ; 23(7): 1437-46, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25744190

ABSTRACT

A series of perbutyrylated glycosides of podophyllotoxin and its derivatives were synthesized and evaluated for their antitumor activity in vitro. Most of them exhibit cytotoxic activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Among the synthesized compounds, epipodophyllotoxin α-d-galactopyranoside 8b, epipodophyllotoxin α-d-arabinopyranoside 8e, and podophyllotoxin ß-d-glucopyranoside 11a show the highest potency of anticancer activity with their IC50 values ranging from 0.14 to 1.69µM. Structure activity relationship analysis indicates that the type of glycosidic linkage, the configuration at C-4 of the podophyllotoxin scaffold, and the substitution at 4'-position (OH vs OCH3) can all have significant effect on the potency of their anticancer activity. Several compounds are more active than the control drugs Etoposide and Cisplatin, suggesting their potential as anticancer agents for further development.


Subject(s)
Antineoplastic Agents/chemical synthesis , Glycosides/chemical synthesis , Podophyllotoxin/chemical synthesis , HL-60 Cells , Humans , Inhibitory Concentration 50 , MCF-7 Cells
11.
Eur J Med Chem ; 80: 267-77, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24793877

ABSTRACT

According to the structure-activity relationship, drug combination principle and bioisosterism, a series of the novel esterification and amination 4'-demethylepipodophyllotoxin derivates were rationally designed in order to discover the potential antitumor prodrug. And then these compounds were tested by the drug-topoisomerase II docking models for virtual screening. Thus, twelve target compounds were screened out and synthesized. Most of compounds exhibited promising in vitro anti-tumor activity, particularly 4-N-tris(hydroxymethyl)metylaminomethane-4-deoxy-4'-demethylepipodophyllotoxin (Compound 1). The anti-tumor activity of Compound 1 against the tumor cell lines BGC-823 (i.e., the IC50 value of 5.35 ± 0.77 µM), HeLa (i.e., the IC50 value of 160.48 ± 14.50 µM), and A549 (i.e., the IC50 value of 13.95 ± 5.41 µM) was significantly improved by 706%, 31% and 900% than that of etoposide (i.e., the IC50 values of 43.74 ± 5.13, 209.90 ± 13.42, and 139.54 ± 7.05 µM), respectively. Moreover, the IC50 value of Compound 1 against the normal human cell line HK-2 (i.e., 16.3 ± 3.77 µM) was 78% lower than that of etoposide (i.e., 9.17 ± 1.58 µM). Compound 1 could diminish the relaxation reaction topoisomerase II DNA decatenation at a concentration of 10 µM and induce BGC-823 apoptosis by breaking DNA double-strand and activating ATM/ATR signaling pathways.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/metabolism , DNA Topoisomerases, Type II/metabolism , Drug Design , Podophyllotoxin/analogs & derivatives , Signal Transduction/drug effects , Amination , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Catalytic Domain , Cell Line, Tumor , DNA Topoisomerases, Type II/chemistry , Humans , Molecular Docking Simulation , Podophyllotoxin/chemical synthesis , Podophyllotoxin/chemistry , Podophyllotoxin/metabolism , Podophyllotoxin/pharmacology , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/metabolism , Topoisomerase II Inhibitors/pharmacology
12.
Bioorg Med Chem ; 22(11): 2998-3007, 2014 Jun 01.
Article in English | MEDLINE | ID: mdl-24775914

ABSTRACT

A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4'-demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential antitumor prodrug. Firstly, according to the structure-activity relationship, drug combination principle and bioisosterism, the -COO- and the -NH- bond substituents at the 4 position of cycloparaffin would be a great modification direction to improve antitumor activity of 4'-demethylepipodophyllotoxin (DMEP). Secondly, from the prodrug principle view, the esterification and amidation at the C-4 position of DMEP would be two useful structure modifications for improve solubility. Thirdly, from the activity pocket in Topo II-DNA cleavage complex point of view, a series of heterocyclic with pharmacological activity were chosen as module for improving antitumor activity by binding with Topo II. Finally, nine novel esterification and amidation DMEP derivates were designed and synthesized for the potential Topo II inhibitors with the superior biological activity. All the novel compounds exhibited promising in vitro antitumor activity, especially 4-O-(2-pyrazinecarboxylic)-4'-demethylepipodophyllotoxin (compound 1). The antitumor activity of compound 1 against tumor cell line HeLa (i.e., the IC50 value of 0.60 ± 0.20 µM), A549 (i.e., the IC50 value of 3.83 ± 0.08 µM), HepG2 (i.e., the IC50 value of 1.21 ± 0.05 µM), and BGC-823 (i.e., the IC50 value of 4.15 ± 1.13 µM) was significantly improved by 66, 16, 12, and 6 times than that of the clinically important podophyllum anticancer drug etoposide (i.e., the IC50 values of 15.32 ± 0.10, 59.38 ± 0.77, 67.25 ± 7.05, and 30.74 ± 5.13 µM), respectively. Compound 1 could arrest HeLa cell cycle G2/M and induce apoptosis by strongly diminishing the relaxation reaction of Topo II-DNA decatenation. The correctness of rational drug design was strictly demonstrated by the bioactivity test.


Subject(s)
Antineoplastic Agents/pharmacology , DNA, Neoplasm/drug effects , Drug Design , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/pharmacology , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Hep G2 Cells , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry
13.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-550541

ABSTRACT

The antiumor activity of a new podophyllotoxin spin-labeled derivative, 4 -C 4 "-( 2 ", 2", C", 6"-tetramethyl- 1 "-piperidinyoxy ) amino]-4'-demethylepipodophyllotoxin ( GP-7 ) was studied. It was found that the growth of transplanted mouse tumors S180, HePS and Lewis lung cancer was markedly inhibited by GP-7. At a dose of 7.5-20 mg/kg, the inhibition rates of it against Sl80, HePS and Lewis lung cancer were 36.0-58.4, 29.6-60.0, and 27.2-46.5 % respectively. The toxicity of GP-7 was low, as indicated by the LD50 value of 231.2 mg/kg which was 3.3 times higher than that of etoposide ( VP-16 ) . On the other hand, the effects of GP-7 on spleen index and thymus index of mice bearing S180 tumor were remarkably lower than that of VP-16. In vitro GP-7 exhibited marked inhibition effects against L1210 and SGC-7901 cells. After exposure of L1210 cells to GP-7 and VP-16 5 mg/L for 24 h, the. inhibition rates were 75.5 and 73.6 %. after exposure of SGC-7901 cells to GP-7 and VP-16 5 mg/L for 72 h, the inhibition rates were 81.4 and 84.2 %. The new podophyllotoxin derivative GP-7 was similar to its structure analogues, clinical drug VP-16, in antitumor activity, while the toxicity of it was much lower than that of VP-16.

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