Podophyllotoxin Analogues Research Articles

ChemInform Abstract: Design and Synthesis of C‐Ring Lactone‐ and Lactam‐Based Podophyllotoxin Analogues as Anticancer Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Studies on Pyrrolidinone. Synthesis of Aza Analogues of Podophyllotoxin and Related Compounds.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Molecular Modeling and Structure-Activity Relationship of Podophyllotoxin and Its Congeners

A quantitative structure-activity relationship (QSAR) model has been developed between cytotoxic activity and structural properties by considering a data set of 119 podophyllotoxin analogs based on 2D and 3D structural descriptors. A systematic stepwise searching approach of zero tests, a missing value test, a simple correlation test, a multicollinearity test, and a genetic algorithm method of variable selection was used to generate the model. A statistically significant model (r(train)(2) = 0.906; q(cv)(2) = 0.893) was obtained with the molecular descriptors. The robustness of the QSAR model was characterized by the values of the internal leave-one-out cross-validated regression coefficient (q(cv)(2)) for the training set and r(test)(2) for the test set. The overall root mean square error (RMSE) between the experimental and predicted pIC(50) value was 0.265 and r(test)(2) = 0.824, revealing good predictability of the QSAR model. For an external data set of 16 podophyllotoxin analogs, the QSAR model was able to predict the tubulin polymerization inhibition and mechanistically cytotoxic activity with an RMSE value of 0.295 in comparison to experimental values. The QSAR model developed in this study shall aid further design of novel potent podophyllotoxin derivatives.

A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

The powerful inhibitory activity of podophyllotoxin (a natural product) on cell growth led to the development of clinically useful anticancer agents such as etoposide, teniposide, and etopophos. Although, these podophyllotoxin derivatives show good clinical effects against various cancers, its use often results in various undesired side effects, drug resistance, and cytotoxicity towards the normal cells. In order to overcome these limitations, it is essential to search new podophyllotoxin analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for the cancer patients. With this purpose, the cytotoxicity data of two series of podophyllotoxin derivatives against four different cancer cell lines was used to develop 4 QSAR models. Hydrophobic property of the molecules was found one of the most important determining factors for their activity. The developed QSAR models showed a good correlative and predictive abilities having r(2) = 0.960 to 0.836 and q(2) = 0.911 to 0.705. On the basis of QSAR 1, two compounds (10-10 and 10-11) are suggested as potential synthetic targets. Statistical diagnostics and internal validation (cross validation and Y-randomization) tests have validated all the QSAR models. These QSAR models could be useful in the rational design of potential drug molecules with an enhanced inhibitory potency.

Podophyllotoxin analogues active versus Trypanosoma brucei

In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with Log P values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.

Design and Synthesis of C-Ring Lactone- and Lactam-Based Podophyllotoxin Analogues as Anticancer Agents

A series of novel podophyllotoxin (PDT) analogues was synthesized in which the lactone moiety was shifted to C ring. Some of the derivatives were also synthesized with modified A ring. Analogues 23 and 25 exhibited potent in vitro cytotoxicity against colon cancer (CaCO(2)) cell line. p-Demethylated E-ring analogues exhibited better potency than the corresponding methylated analogues. These analogues showed toxicity comparable to PDT against human erythrocytes albeit at much higher concentrations (100 microg/ml) than their cytotoxicity values.

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Podophyllotoxin and its analogues have important therapeutic value in the treatment of cancer, due to their ability to induce apoptosis in cancer cells in a proliferation-independent manner. These ligands bind to colchicine binding site of tubulin near the α- and β-tubulin interface and interfere with tubulin polymerization. The binding free energies of podophyllotoxin-based inhibitors of tubulin were computed using a linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model. A training set of 76 podophyllotoxin analogues was used to build a binding affinity model for estimating the free energy of binding for 36 inhibitors (test set) with diverse structural modifications. The average root mean square error (RMSE) between the experimental and predicted binding free energy values was 0.56 kcal/mol which is comparable to the level of accuracy achieved by the most accurate methods, such as free energy perturbation (FEP) or thermodynamic integration (TI). The squared correlation coefficient between experimental and SGB–LIE estimates for the free energy for the test set compounds is also significant ( R 2 = 0.733). On the basis of the analysis of the binding energy, we propose that the three-dimensional conformation of the A, B, C and D rings is important for interaction with tubulin. On the basis of this insight, 12 analogues of varying ring modification were taken, tested with LIE methodology and then validated with their experimental potencies of tubulin polymerization inhibition. Low levels of RMSE for the majority of inhibitors establish the structure-based LIE method as an efficient tool for generating more potent and specific inhibitors of tubulin by testing rationally designed lead compounds based on podophyllotoxin derivatization.

Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues

Podophyllotoxin and its structural derivatives, a class of tubulin polymerization inhibitors, have been the objective of numerous studies to prepare better and safer anti-cancer drugs. A library of podophyllotoxin analogues has been designed consisting of 154 analogues. Their molecular interactions and binding affinities with tubulin protein (1SA1) have been studied using the docking-molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Quantitative structure activity relationships were developed between the cytotoxic activity (pIC(50)) of these compounds and molecular descriptors like docking score and binding free energy. For both the cases the r(2) was in the range of 0.642-0.728 indicating good data fit and r(cv)(2) was in the range of 0.631-0.719 indicating that the predictive capabilities of the models were acceptable. In addition, a linear correlation was observed between the predicted and experimented pIC(50) for the validation data set with correlation coefficient r(2) of 0.806 and 0.887, suggesting that the docked structure orientation and the interaction energies are reasonable. Low levels of root mean square error for the majority of inhibitors establish the docking and Prime/MM-GBSA based prediction model as an efficient tool for generating more potent and specific inhibitors of tubulin protein by testing rationally designed lead compounds based on podophyllotoxin derivatization.

ChemInform Abstract: Design, Synthesis, and Biological Testing of 4β‐[(4‐Substituted)‐1,2,3‐triazol‐1‐yl]podophyllotoxin Analogues as Antitumor Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of novel derivatives of bispodophyllotoxin as potential antineoplastic agents–Part XVI1

Podophyllotoxin and related analogs present numerous challenges associated with optimal antitumor activity and severe unpredictable toxicity. In an attempt to find biorational podophyllotoxin-related drug, two moieties of podophyllotoxin have been linked at C4-position by a simple modification of the carbodiimide procedure to provide novel bispodophyllotoxin analogs (4a–4e) and their structural information was extensively characterized by using 1H-NMR, IR, and HRMS. 1For part XV: see Y.Q. Liu, L.Yang, X. Tian. Podophyllotoxin: Current Perspectives, Current Bioactive Compounds, 3 37 (2007).

Design, Synthesis, and Biological Testing of 4β‐[(4‐Substituted)‐1,2,3‐triazol‐1‐yl]podophyllotoxin Analogues as Antitumor Agents

A series of 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin analogues have been synthesized with high regio-selectivity by employing copper(I)-catalyzed 1,3-dipolar cycloaddition of 1-O-propargyl monosaccharides with C4beta-azido podophyllotoxin and C4beta-azido-4'-O-demethyl podophyllotoxin. All the compounds were evaluated for their anticancer activity against a panel of six human cancer cell lines. Among these, 4'-O-demethyl podophyllotoxin congeners are showing promising anticancer activity mainly against HCT-15 (colon) and DU-145 (prostate) cells.

Discovery and Investigation of Antiproliferative and Apoptosis-Inducing Properties of New Heterocyclic Podophyllotoxin Analogues Accessible by a One-Step Multicomponent Synthesis

Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracyclic dihydropyridopyrazoles. Libraries of these structurally simple analogues are prepared by a straightforward one-step multicomponent synthesis and demonstrated to display antiproliferative properties in a number of human cancer cell lines. These new heterocycles potently induce apoptosis in cancerous Jurkat cells even after a short 24 h exposure. In contrast, no apoptosis is detected in primary lymphocytes under the same treatment conditions. The ease of synthesis and encouraging biological activities make the presented library of dihydropyridopyrazoles promising new leads in anticancer drug design.

Sesquiterpenoids and Cytotoxic Lignans from the Bark of Libocedrus chevalieri

Investigation of an EtOAc extract of the bark of Libocedrus chevalieri led to the isolation of a new cytotoxic lignan, 5-methoxy-4-epipodophyllotoxin (1), and three known podophyllotoxin analogues, 5-methoxypodophyllotoxin, 5-methoxypodophyllotoxin-4-O-beta-D-glucoside, and podophyllotoxin-4-O-beta-D-glucoside. Six sesquiterpenoids and a diterpenoid were also obtained. Of these, compounds 2-4 are new sesquiterpenoids, named libocedrines A-C, and 3beta-hydroxyilicic alcohol was isolated for the first time from a higher plant. Structures of the new compounds were determined on the basis of spectroscopic methods. Cytotoxicity of the isolated compounds against KB and L1210 cells and their effects on tubulin assembly were evaluated.

Synthesis and Characterization of New Diketone Analogues of Podophyllotoxin

The new compounds 6,6a‐dihydro‐2,3‐dimethoxy‐9‐nitro–11bH benzo [C]‐fluoren 5,7‐dione, 6,6a‐dihydro‐2,3‐dimethoxy‐9‐chloro–11bH benzo[C]‐fluoren‐5,7‐dione and 6,6a‐dihydro‐2,3‐dimethoxy‐9‐fluoro–11bH benzo[C]‐fluoren‐5,7‐ dione were synthesized in high yields. They are analogues of naturally occurring lignan podophyllotoxin which exhibits anticancer activity. They are very essential to study anticancer activity.

Podophyllotoxin: Current Perspectives

Podophyllotoxin is a naturally occurring lignan with important antineoplastic and antiviral properties and supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their bioactivity, the podophyllotoxin analogues have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of podophyllotoxin-based multidrug regimens, which are showing important activity in several malignancies, and many of its related analogues will complement conventional pharmaceuticals in treatment, prevention and diaganosis of disease, while at the same time adding value to agriculture. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of etoposide-based multidrug regimens, which are showing important activity in several malignancies. Extensive structural modifications of podophyllotoxin have been performed in order to obtain more potent and less toxic antitumour agents, which resulted in the widespread clinical introduction of two semisynthetic glucoconjugate analogues of etoposide and teniposide and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better podophyllotoxin-based strategies for treatment of malignant disease are likely to evolve. This review provides a detailed discussion of research advances in the synthetic and medicinal chemistry of podophyllotoxin, and addresses the short history and pharmacological action of these compounds and further outlines the preclinical development and clinical trials of drugs in the pipeline and marketing approval. Finally, a systemic evaluation of novel and important analogues of podophyllotoxin and their contribution to the current structure-activity profile are considered. It is hoped that this review will be able to address the contributions of podophyllotoxin-related research to overall drug discovery and development and the role that this field will play in future. Keywords: Reviews, podophyllotoxin, short chronology, biological activity, medicinal application, mechanism of actions, chemical modification, structure-activity relationships.

Structural simplification of bioactive natural products with multicomponent synthesis: Dihydropyridopyrazole analogues of podophyllotoxin

A three-component condensation of 5-amino-3-methylpyrazole, tetronic acid, and various aromatic, heteroaromatic, and aliphatic aldehydes leads to the formation of dihydropyridopyrazole analogues of a cytotoxic lignan podophyllotoxin. This new heterocyclic scaffold-based library allows a drastic reduction of the structural complexity of the natural product with the retention of its potent cytotoxic properties. Similarly to podophyllotoxin, the presented analogues induce apoptosis in Jurkat cells.

Synthesis and anti-HIV-1 activities of novel podophyllotoxin derivatives

In order to explore the range of biological activities of the podophyllotoxin compound class, a novel series of derivatives of podophyllotoxin, which were conjugates containing stavudine and different structural podophyllotoxin analogues, were designed, synthesized, and evaluated for their anti-HIV-1 activities in vitro. Among these compounds, 19d and 19c showed the highest anti-HIV-1 activities with EC 50 values of 0.17 and 0.29 μM and TI values of 466.9 and 354.5, respectively.

Oxalone and Lactone Moieties of Podophyllotoxin Exhibit Properties of Both the B and C Rings of Colchicine in Its Binding with Tubulin

Thermodynamics of podophyllotoxin binding to tubulin and its multiple points of attachment with tubulin has been studied in detail using isothermal titration calorimetry. The calorimetric enthalpy of the association of podophyllotoxin with tubulin is negative and occurs with a negative heat capacity change (DeltaC(p) = -2.47 kJ mol(-)(1) K(-)(1)). The binding is unique with a simultaneous participation of both hydrophobic and hydrogen-bonding forces with unfavorable negative entropic contribution at higher temperature, favored with an enthalpy-entropy compensation. Interestingly, the binding of 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone (AC, a colchicine analogue without the B ring) with tubulin is enthalpy-favored. However, the podophyllotoxin-tubulin association depending upon the temperature of the reaction has a favorable entropic and enthalpic component, which resembles both B- and C-ring properties of colchicine. On the basis of the crystal structure of the podophyllotoxin-tubulin complex, distance calculations have indicated a possible interaction between threonine 179 of alpha-tubulin and the hydroxy group on the D ring of podophyllotoxin. To confirm the involvement of the oxalone moiety as well as the lactone ring of podophyllotoxin in tubulin binding, analogues of podophyllotoxin are synthesized with methoxy substitution at the 4' position of ring D along with its isomer and another analogue epimerized at ring E. From these results, involvement of oxalone as well as the lactone ring of the drug in a specific orientation inclusive of ring A is indicated for podophyllotoxin-tubulin binding. Therefore, podophyllotoxin, like colchicine, behaves as a bifunctional ligand having properties of both the B and C rings of colchicine by making more than one point of attachment with the protein tubulin.

Synthesis and Biological Activity of New 4β-N-Heteroaryl Analogues of Podophyllotoxin

Some new 4β-N-heteroaryl analogues of podophyllotoxin have been prepared by employing Red Phosphorous/I2 reagent system. These 4β-N-heteroaryl analogues have been evaluated for their cytotoxicity against six human cancer cell lines and some representative ones have shown promising anticancer activity. Keywords: Epipodophyllotoxin, benzothiazoles, pyrimidines, anticancer activity

Determination of Podophyllotoxin and 4′-Demethylepipodophyllotoxin by Capillary Electrophoresis

A new simple, rapid and sensitive capillary zone electrophoresis (CZE) method has been developed for the simultaneous separation and determination of the anticancer active compounds podophyllotoxin (PPT) and 4′-demethylepipodophyllotoxin (DMEP) in ethanol extracts of the roots of Sinopophyllum emodi (Wall) Ying, and the roots, stems, leaves and fibrils of Dysosma versipellis (Hance) M. cheng. PPT and DMEP could be completely separated and sensitively determined at 214 nm within 12.5 min using 25 mM borate with pH 10.80 as running buffer (applied voltage 20 kV, temperature 20 °C, injection time 5 s). The linear range for the determination of PPT and DMEP were 1.5–171.0 μg mL−1 and 5.0–136.0 μg mL−1 with RSD of the relative migration time for PPT and DMEP of 1.50 and 3.26, and of the relative peak area of 0.82 and 1.13, respectively. The results showed that the method had requisite selectivity, sensitivity, reproducibility and wide linear range for the application to the rapid separation and accurate determination of PPT and DMEP in podophyllum plants. Furthermore, this is the first report about the analysis of podophyllotoxin analogues by CE.