Nephrotoxicity assessment of podophyllotoxin-induced rats by regulating PI3K/Akt/mTOR-Nrf2/HO1 pathway in view of toxicological evidence chain (TEC) concept.

Adverse reactions to traditional Chinese medicine have hindered the healthy development and internationalization process of the traditional Chinese medicine industry. The critical issue that needs to be solved urgently is to evaluate the safety of traditional Chinese medicine systematically and effectively. Podophyllotoxin (PPT) is a highly active compound extracted from plants of the genus Podophyllum such as Dysosma versipellis (DV). However, its high toxicity and toxicity to multiple target organs affect the clinical application, such as the liver and kidney. Based on the concurrent effects of PPT's medicinal activity and toxicity, it would be a good example to conduct a systematic review of its safety. Therefore, this study revolves around the Toxicological Evidence Chain (TEC) concept. Based on PPT as the main toxic constituent in DV, observe the objective toxicity impairment phenotype of animals. Evaluate the serum biochemical indicators and pathological tissue sections for substantial toxic damage results. Using metabolomics, lipidomics, and network toxicology to evaluate the nephrotoxicity of PPT from multiple perspectives systematically. The results showed that PPT-induced nephrotoxicity manifested as renal tubular damage, mainly affecting metabolic pathways such as glycerophospholipid metabolism and sphingolipid metabolism. PPT inhibits the autophagy process of kidney cells through the PI3K/Akt/mTOR and Nrf2/HO1 pathways and induces the activation of oxidative stress in the body, thereby causing nephrotoxic injury. This study fully verified the feasibility of the TEC concept for the safety and toxicity evaluation of traditional Chinese medicine. Provide a research template for systematically evaluating the safety of traditional Chinese medicine.

In Vitro Anti-Tubulin Activity on MCF10A Cell Line and In Silico Rigid/Semiflexible-Residues Docking, of Two Lignans from Bursera Fagaroides var. Fagaroides.

Podophyllotoxins are natural lignans with known cytotoxic activity on several cell lines. The structural basis for their actions is mainly by the aryltetralin-lignan skeleton. Authors have proposed a cytotoxic mechanism of podophyllotoxins through the topoisomerase-II inhibition activity; however, several studies have also suggested that podophyllotoxins can inhibit the microtubules polymerization. In this work, the two possible mechanisms of action of two previously isolated compounds from the stem bark of Bursera fagaroides var. fagaroides: acetylpodophyllotoxin (1) and 5'-desmethoxydeoxypodophyllotoxin (2), was analyzed. An in vitro anti-tubulin epifluorescence on the MCF10A cell line and enzymatic topoisomerase II assays were performed. The binding affinities of compounds 1 and 2 in the colchicine binding site of tubulin by using rigid- and semiflexible-residues were calculated and compared using in silico docking methods. The two lignans were active by the in vitro anti-tubulin assay but could not inhibit TOP2 activity. In the in silico analysis, the binding modes of compounds into both rigid- and semiflexible-residues of tubulin were predicted, and only for the semiflexible docking method, a linear correlation between the dissociation constant and IC50 previously reported was found. Our results suggest that a simple semiflexible-residues modification in docking methods could provide an in vitro correlation when analyzing very structurally similar compounds.

[Research progress in biosynthesis of podophyllotoxin and its derivatives].

Podophyllotoxin (PTOX) is an aryl-tetralin lignan of plant origin found in some species of Podophyllum such as Dysosma versipellis, Diphylleia sinensis, and Sinopodophyllum hexandrum. Etoposide and teniposide are produced semisynthetically from PTOX and used clinically to treat several forms of cancer. As a typical representative of new drug discovery from natural products, the production of PTOX solely depends on extraction from plants, resulting in severe contradiction between supply and demand. With the advantages of unconstrained resources and eco-friendly reaction conditions, biosynthesis method has become a trend in the production of PTOX and its derivatives. In this review, we summarize the research progress of PTOX biosynthesis in plants and expound the functions of the key enzymes as well as their subcellular location. The synthetic biology for production of PTOX intermediates in a tobacco chassis is also introduced. Finally, the heterologous expression and biotransformation of PTOX in microorganisms is summarized, which sets the foundation for the efficient microbial production of PTOX using cell factories.

Enhanced effects and mechanisms of Syngonium podophyllum-Peperomia tetraphylla co-planting on phytoremediation of low concentration uranium-bearing wastewater.

To improve the remediation efficiency of plants on low concentration uranium-bearing wastewater and clarify its strengthening mechanism, Syngonium podophyllum-Peperomia tetraphylla co-planting system was established, the enhanced effects of plants interaction on uranium removal were investigated, the chemical forms, valence states, and subcellular distribution of uranium in plants were confirmed, and the mechanisms of alleviating uranium stress by plants interaction were revealed. In Syngonium podophyllum-Peperomia tetraphylla co-planting system, the total amount of ethanol-extracted uranium and deionized water-extracted uranium with higher toxicity in their roots were reduced by 10.30% and 7.17%, respectively, which reduced the toxicity of uranium to plants. Plants interaction can inhibit the reduction of U(VI) in the root of Peperomia tetraphylla, which is conducive to the transport of uranium from roots to shoots. In addition, uranium in plants mainly existed in the cell wall (54.44%-66.52%) and the soluble fraction (23.85%-32.89%). These results indicated that Syngonium podophyllum and Peperomia tetraphylla co-planting can enhance their effects of uranium removal by alleviating uranium stress with the cell wall immobilization and vacuole compartmentation, improving biomass of plants, increasing bioaccumulation factor and translocation factor of uranium.

Insecticidal activity of twin compounds from podophyllotoxin and cytisine.

To explore natural-product-based insecticide candidates, and high value-added application of natural plants in agriculture, a series of twin compounds were prepared from two natural products podophyllotoxin and cytisine, which are isolated from the plants Podophyllum hexandrum and Thermopsis lanceolata, respectively. Compounds IIa (X = Cl, Y = R1 = R2 = H), IIIc (X = Y = R1 = R2 = Cl) and IVd (X = R1 = R2 = Br, Y = H) exhibited >2-fold potent insecticidal activity of podophyllotoxin against armyworm with FMRs greater than 60%. SARs were also observed. It is noteworthy that the idea of twin insecticides was addressed for the first time. We hope this idea will be conducive to design new twin insecticidal agents, and lay the foundation for future high value-added application of the plants P. hexandrum and T. lanceolata as potentially botanical pesticides in agriculture.

Podophyllotoxin: History, Recent Advances and Future Prospects.

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions.

Dirigent Proteins Guide Asymmetric Heterocoupling for the Synthesis of Complex Natural Product Analogues.

Phenylpropanoids are a class of abundant building blocks found in plants and derived from phenylalanine and tyrosine. Phenylpropanoid polymerization leads to the second most abundant biopolymer lignin while stereo- and site-selective coupling generates an array of lignan natural products with potent biological activity, including the topoisomerase inhibitor and chemotherapeutic etoposide. A key step in etoposide biosynthesis involves a plant dirigent protein that promotes selective dimerization of coniferyl alcohol, a common phenylpropanoid, to form (+)-pinoresinol, a critical C2 symmetric pathway intermediate. Despite the power of this coupling reaction for the elegant and rapid assembly of the etoposide scaffold, dirigent proteins have not been utilized to generate other complex lignan natural products. Here, we demonstrate that dirigent proteins from Podophyllum hexandrum in combination with a laccase guide the heterocoupling of natural and synthetic coniferyl alcohol analogues for the enantioselective synthesis of pinoresinol analogues. This route for complexity generation is remarkably direct and efficient: three new bonds and four stereocenters are produced from two different achiral monomers in a single step. We anticipate our results will enable biocatalytic routes to difficult-to-access non-natural lignan analogues and etoposide derivatives. Furthermore, these dirigent protein and laccase-promoted reactions of coniferyl alcohol analogues represent new regio- and enantioselective oxidative heterocouplings for which no other chemical methods have been reported.

Medicinal importance of Papra (Podophyllum hexandrum Royle) in Unani System of Medicine.

Podophyllum hexandrum Royle [=Sinopodophyllum hexandrum (Royle) T.S. Ying] is an important, endemic medicinal plant species of Himalaya. It is used in Unani System of Medicine under the name of 'Papra'. The drug was not mentioned in previous literatures, but the first time it introduced in Unani Medicine by a great scholar Hakim Najmul Ghani. He has mentioned its uses and benefits in his classical book Khazainul Advia. In Unani Medicine the plant species has been used to treat various ailments like constipation, fever, jaundice, liver disorders, syphilis, diseases of lymph glands etc. In Kashmir Himalaya it is used to treat various diseases by local medicinemen, but now it is listed in rare drugs. Various pharmacological studies have been done such as antioxidant, antimicrobial, anti-inflammatory, antifungal, radio-protective etc., recently it has also been reported that podophyllotoxin or podophyllin can be used to treat some forms of cancers also.

Research progress in biosynthesis of podophyllotoxin and its derivatives / 生物工程学报

Podophyllotoxin (PTOX) is an aryl-tetralin lignan of plant origin found in some species of Podophyllum such as Dysosma versipellis, Diphylleia sinensis, and Sinopodophyllum hexandrum. Etoposide and teniposide are produced semisynthetically from PTOX and used clinically to treat several forms of cancer. As a typical representative of new drug discovery from natural products, the production of PTOX solely depends on extraction from plants, resulting in severe contradiction between supply and demand. With the advantages of unconstrained resources and eco-friendly reaction conditions, biosynthesis method has become a trend in the production of PTOX and its derivatives. In this review, we summarize the research progress of PTOX biosynthesis in plants and expound the functions of the key enzymes as well as their subcellular location. The synthetic biology for production of PTOX intermediates in a tobacco chassis is also introduced. Finally, the heterologous expression and biotransformation of PTOX in microorganisms is summarized, which sets the foundation for the efficient microbial production of PTOX using cell factories.

The Effect of p53-R249S on the Suppression of Hepatocellular Carcinoma Cells Survival Induced by Podophyllum Derivatives.

BACKGROUND: Hepatocellular Carcinoma (HCC), the second leading cause of cancer-related mortality with over half a million new cases diagnosed annually in the world, accounts for nearly 70% of cancer deaths in parts of Asia and Africa. Podophyllum, one of the important members of the lignane class of natural products derived from plants in Podophyllum peltatum L., has been shown to suppress tumor growth in various cancers. However, the effects of Podophyllum compounds on HCC and the mechanisms for its tumor-suppressive function remain unknown. METHODS: A molecular docking study was employed to the analysis of the interaction between compounds and their targeted proteins. Cell proliferation was measured by MTT assay. Western blot analysis was used to evaluate protein expression. qRT-PCR was performed to assess RNA expression. RESULTS: Molecular docking analysis was consistent with the beneficial effect of fluorine atom substituent in the 3-position of 2-aminopyridine in our previous study. Also, P-3F and D-3F displayed the most potent cytotoxicities against PLC/PRF/5 with p53-R249S and weakest inhibition of L02 (normal liver cell) growth. However, these derivatives had no effect on the suppression of HepG2 (wild-type p53) and Hep3B (p53-null) proliferation significantly. Further study showed that both compounds increase γ-H2AX expression in PLC/PRF/5 cell, along with repression of the c-Myc activation, purportedly by induction of p53 level and transcriptional activation. CONCLUSION: The results suggested that podophyllum derivatives containing fluorine atom in the 3-position of 2- aminopyridine could inhibit the growth of HCC harboring p53-R249S by restoring the activity of p53 with decreasing the level of c-Myc.

Combined In Vitro Studies and in Silico Target Fishing for the Evaluation of the Biological Activities of Diphylleia cymosa and Podophyllum hexandrum.

This paper reports the in silico prediction of biological activities of lignans from Diphylleia cymosa and Podophyllum hexandrum combined with an in vitro bioassays. The extracts from the leaves, roots and rhizomes of both species were evaluated for their antibacterial, anticholinesterasic, antioxidant and cytotoxic activities. A group of 27 lignans was selected for biological activities prediction using the Active-IT system with 1987 ligand-based bioactivity models. The in silico approach was properly validated and several ethnopharmacological uses and known biological activities were confirmed, whilst others should be investigated for new drugs with potential clinical use. The extracts from roots of D. cymosa and from rhizomes and roots of P. hexandrum were very effective against Bacillus cereus and Staphylococcus aureus, while podophyllotoxin inhibited the growth of Staphylococcus aureus and Escherichia coli. D. cymosa leaves and roots showed anticholinesterasic and antioxidant activities, respectively. The evaluated extracts showed to be moderately toxic to THP-1 cells. The chromatographic characterization indicated that podophyllotoxin was the major constituent of P. hexandrum extract while kaempferol and its hexoside were the main constituents of D. cymosa leaves and roots, respectively. These results suggest that the podophyllotoxin could be the major antibacterial lignan, while flavonoids could be responsible for the antioxidant activity.

Synthesis and anticancer activity of dimeric podophyllotoxin derivatives.

BACKGROUND: Podophyllotoxin 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 4ß-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. METHODS: Two 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. 4ß-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. RESULTS: A 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. CONCLUSION: The 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.

Involvement of RPL11 in the enhancement of P53 stability by a podophyllum derivative, a topoisomerase II inhibitor.

In previous work, we presented experimental and theoretical evidence that D-3F or 4-N-(2-Amino-3-fluoropyridine)-4-deoxidation-4'-demethylepipofophyllotoxin induced G2 /M phase arrest and apoptosis, purportedly by increasing the expression of P53. However, the precise mechanism of D-3F action is currently unknown. Here, we investigated the mechanism by which D-3F treatment induces increased expression of P53. This study showed that D-3F definitively inhibited the activity of topoisomerase II in a dose-dependent manner and resulted in DNA damage. The results were in overall agreement with modeling and docking studies performed on D-3F. In addition, D-3F increased the levels of P53 and P21 in HeLa cells in a dose-dependent manner, this in turn prolonged the half-life of P53. Taken together, these data suggested that D-3F-mediated transient enhancement of P53 stabilization may be critical for the P53/P21 signalling pathway leading to G2 /M phase arrest on HeLa cells. Furthermore, D-3F downregulated the phosphorylation of E3 ubiquitin-protein ligase murine double minute 2 (Mdm2) at Ser166, inhibited Mdm2-mediated ubiquitination of P53, and released 60S ribosomal protein L11 (RPL11) from the nucleolus into the nucleoplasm. To conclude, the topoisomerase II inhibitor D-3F causes P53 to accumulate in HeLa cell lines by enhancing its stability as a result of DNA-damage induced RPL11 relocalization and subsequent blocking of the P53-Mdm2 feedback loop.

Toxicity and Larvicidal Activity of Podophyllum-Based Lignans Against Aedes aegypti (Diptera: Culicidae).

Aedes aegypti L. (Diptera: Culicidae) is a mosquito species that has adapted to urban environments and is the main vector of dengue viruses. Because of the increasing incidence of dengue, a more environmentally acceptable insecticide needs to be found. Natural products have been and continue to be an important source of leading compounds that can be modified in order to develop new drugs. The lignan family of natural products includes compounds with a diverse spectrum of biological activity. Podophyllotoxin and its related lignans represent an exciting class of natural products that can be targeted at different types of biological activity and are therefore worth exploring further. This study had the aim of evaluating the larvicidal activity of an ethanolic extract from the rhizomes and roots of Podophyllum hexandrum (PM-3) and its isolated lignans, podophyllotoxone (1) and desoxypodophyllotoxin (2), on the larvae of the mosquito vector Ae. aegypti. The PM-3 extract and the compounds (1) and (2) were dissolved in a mixture of acetone and dimethylsulfoxide at final concentrations of 1, 10, 30, 50, 100, and 200 µg/ml. After dilution, the solutions were applied (µg/ml) to the larvae-rearing medium. Overall, the ethanolic extract from the rhizomes and roots of P. hexandrum and the compounds (1) and (2) showed larvicidal activity against the larvae of Ae. aegypti According to the results from this study, it can be concluded that podophyllotoxone (1) and desoxypodophyllotoxin (2) exhibited significant toxicity toward Ae. aegypti larvae.

Construction of the Syngonium podophyllum-Pseudomonas sp. XNN8 Symbiotic Purification System and Investigation of Its Capability of Remediating Uranium Wastewater.

The endophyte Pseudomonas sp. XNN8 was separated from Typha orientalis which can secrete indole-3-acetic acid and 1-aminocyclopropane-1-carboxylate deaminase and siderophores and has strong resistance to uranium it was then colonized in the Syngonium podophyllum; and the S. podophyllum-Pseudomonas sp. XNN8 symbiotic purification system (SPPSPS) for uranium-containing wastewater was constructed. Afterwards, the hydroponic experiments to remove uranium from uranium-containing wastewater by the SPPSPS were conducted. After 24 days of treatment, the uranium concentrations of the wastewater samples with uranium concentrations between 0.5 and 5.0 mg/L were lowered to below 0.05 mg/L. Furthermore, the uranium in the plants was assayed using Fourier transform infrared spectroscopy (FTIR) and extended X-ray absorption fine structure (EXAFS) spectroscopy. The Pseudomonas sp. XNN8 was found to generate substantial organic groups in the roots of the Syngonium podophyllum, which could improve the complexing capability of S. podophyllum for uranium. The uranium in the roots of S. podophyllum was found to be the uranyl phosphate (47.4 %) and uranyl acetate (52.6 %).

Comparative whole-transcriptome analysis in Podophyllum species identifies key transcription factors contributing to biosynthesis of podophyllotoxin in P. hexandrum.

Podophyllum species (Podophyllum hexandrum Royle and Podophyllum peltatum) are a major source of deriving anticancer drugs from their major chemical constituent, podophyllotoxin. However, information lacks on regulatory components of podophyllotoxin biosynthesis; therefore, different classes of transcription factors were identified through mining transcriptomes of Podophyllum species and validated through qRT-PCR analysis vis-à-vis podophyllotoxin contents in different tissues/organs of Podophyllum hexandrum. A total of 82, 278, 70, and 90 transcripts were identified in shoots and 89, 273, 72, and 91 transcripts in rhizomes of P. hexandrum transcriptome; 70, 268, 48, and 92 transcripts were in shoots and 58, 245, 41, and 85 transcripts in rhizomes of P. peltatum transcriptome corresponding to bZIP, MYB, WRKY, and bHLH families of transcription factors, which have been shown in regulating biosynthesis of secondary metabolites. Two unique transcripts encoding bHLH and MYB/SANT TFs in shoots of P. peltatum (medp_podpe_41091 and medp_podpe_2547) and bZIP and MYB TFs in rhizomes of P. hexandrum (medp_podhe_163581 and medp_podhe_147614) correlated with podophyllotoxin content. Quantification of podophyllotoxin and comparative expression analysis between high (2.51 %) versus low (0.59) podophyllotoxin content accessions revealed 0.04 to ~16-folds increase in transcripts of transcription factors, thereby further supporting the association of identified transcription factors with podophyllotoxin content. bZIP TF showed the highest transcript abundance (19.60-folds) in P. hexandrum rhizomes (2.51 % podophyllotoxin) compared to shoots (0.01 %). In silico analysis of putative promoter regions of pathway genes in other plant species revealed the presence of sequence elements for MYB and WRKY transcription factors, thereby suggesting their role in controlling the production of podophyllotoxin. A repertoire of additional transcription factors has been provided, which can be functionally validated and used in designing a suitable genetic intervention strategy towards enhanced production of podophyllotoxin.

Synthesis of some ester derivatives of 4'-demethoxyepipodophyllotoxin/2'-chloro-4'-demethoxyepipodophyllotoxin as insecticidal agents against oriental armyworm, Mythimna separata Walker.

Podophyllotoxin is a naturally occurring non-alkaloid toxin isolated from the roots and rhizomes of Podophyllum peltatum and P. hexandrum. In continuation of our program aimed at the discovery and development of natural product-based insecticides, two series of ester derivatives of 4'-demethoxyepipodophyllotoxin/2'-chloro-4'-demethoxyepipodophyllotoxin were prepared. The structures of the target compounds were well characterized by 1H NMR, IR, optical rotation and mp. The precise three-dimensional structural information of 8j was further determined by single-crystal X-ray diffraction. Their insecticidal activity was tested against Mythimna separata Walker. These compounds showed delayed insecticidal activity. Among all derivatives, some compounds showed more potent insecticidal activity than toosendanin against M. separata; especially compounds 8k and 9k exhibited the most potent activity with the final mortality rates of 71.4%. Their structure-activity relationships were discussed.

Biotechnological interventions for harnessing podophyllotoxin from plant and fungal species: current status, challenges, and opportunities for its commercialization.

Podophyllotoxin is an aryltetralin lignan synthesized in several plant species, which is used in chemotherapies for cancers and tumor treatment. More potent semisynthetic derivatives of podophyllotoxin such as etoposide and teniposide are being developed and evaluated for their efficacy. To meet the ever increasing pharmaceutical needs, species having podophyllotoxin are uprooted extensively leading to the endangered status of selective species mainly Sinopodophyllum hexandrum. This has necessitated bioprospection of podophyllotoxin from different plant species to escalate the strain on this endangered species. The conventional and non-conventional mode of propagation and bioprospection with the integration of biotechnological interventions could contribute to sustainable supply of podophyllotoxin from the available plant resources. This review article is focused on the understanding of different means of propagation, development of genomic information, and its implications for elucidating podophyllotoxin biosynthesis and metabolic engineering of pathways. In addition, various strategies for sustainable production of this valuable metabolite are also discussed, besides a critical evaluation of future challenges and opportunities for the commercialization of podophyllotoxin.

Recent Advances in the Chemistry and Biology of Podophyllotoxins.

Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, antispasmogenic, and hypolipidemic activities). This Review provides a survey of podophyllotoxin and its analogues isolated from plants. In particular, recent developments in the elegant total chemical synthesis, structural modifications, biosynthesis, and biotransformation of podophyllotoxin and its analogues are summarized. Moreover, a deoxypodophyllotoxin-based chemosensor for selective detection of mercury ion is described. In addition to the most active podophyllotoxin derivatives in each series against human cancer cell lines and insect pests listed in the tables, the structure-activity relationships of podophyllotoxin derivatives as cytotoxic and insecticidal agents are also outlined. Future prospects and further developments in this area are covered at the end of the Review. We believe that this Review will provide necessary information for synthetic, medicinal, and pesticidal chemistry researchers who are interested in the chemistry and biology of podophyllotoxins.

Podophyllum hexandrum ameliorates endosulfan-induced genotoxicity and mutagenicity in freshwater cyprinid fish crucian carp.

CONTEXT: Medicinal plants continue to act as a repository for novel drug leads with novel mechanisms of action. Podophyllum hexandrum Royale (Berberideceae) treats diverse conditions in folk medicine. OBJECTIVE: The antimutagenic potential of P. hexandrum was evaluated against endosulfan-induced clastogenicity in a piscine model by cytogenetic endpoints. MATERIALS AND METHODS: Podophyllum hexandrum rhizomes were subjected to successive solvent extraction. Fish were exposed to hexane, chloroform, ethyl acetate, methanol and aqueous extracts (15 mg/L each) of plant and endosulfan (0.05 mg/L) alone followed by their combination for antimutagenicity estimates. Chromosomal aberrations (CA) were made from kidney cells and micronuclei (MN) slides from peripheral blood erythrocytes at 48, 72 and 96 h. Antioxidant activity was analyzed by the DPPH assay. Phytochemical analyses were carried out using chromatographic and spectroscopic techniques. RESULTS: Endosulfan induced significant (p < .05) MN, authenticated by scanning electron microscopy, and CA in a time-dependent manner. However, methanol and ethyl acetate extracts revealed ameliorating effects. The column eluted methanolic fraction-2 (ME-F2) showed highest reduction profile of 83 and 84% in CA and MN, followed in its extent (73 and 72%) by ethyl acetate fraction-4 (EE-F4). ME-F2 and EE-F4 showed three and six major peaks when analyzed by GC-MS. To explore possible mechanism of action, ME-F2 showed potent antioxidant potential and strong correlation (R2 = .900) with antimutagenic activity, whereas EE-F4 seemed to act through a different mechanism. DISCUSSION AND CONCLUSION: This study confirms the antimutagenic potential of the subject plant with the identification of some novel compounds, justifying their use in folk medicine, and their corresponding benefit to mankind.