Podophyllotoxin Derivatives Research Articles

Synthesis and Biological Evaluation of 4β‐[(4‐Substituted)‐1,2,3‐triazol‐1‐yl]podophyllotoxins as Potential Anticancer Agents

A series of novel 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives were synthesized by employing Cu(I)-catalyzed click chemistry and evaluated for their anticancer activity against a panel of seven human cancer cell lines (HT-29, HCT-15, 502713, HOP-62, A-549, MCF-7, and SF-295). The compounds 9b, 9c, 9e, 9f, and 9h showed significant cytotoxic activities especially against HT-29, HCT-15, 502713 cell lines.

Relation between the podophyllotoxin derivatives and the cytotoxic activity in Linum scabrellum extracts

Relation between the podophyllotoxin derivatives and the cytotoxic activity in Linum scabrellum extracts

Synthesis and insecticidal activities of novel derivatives of podophyllotoxin: Part XII

In order to find the biorational pesticides, eight novel 4β-substituted phenoxyaniline derivatives of podophyllotoxin have been synthesized with significant stereoselectivity and improved yields by employing the BF 3·Et 2O/NaI reagent system and evaluated for their antifeedant effect against 5th instar larvae of Pieris rapae and effect on the development of 5th instar larvae of P. rapae as well as for insecticidal activity against P. rapae. The antifeedant activities showed that these compounds exhibited less potent than podophyllotoxin. Though these derivatives showed less potent antifeedant activities than podophyllotoxin, they acted as growth development inhibitor to 5th instar larvae of P. rapae, which were found that the animals treated with podophyllotoxin and its derivatives showed moulting disturbances and/or deformities. Also, the insecticidal activity results show that all of these derivatives of PPT showed delayed insecticidal activity, which differs from traditional neurotoxic insecticides. Among them, compounds possessing a 4β-phenoxyaniline moiety substituted (CO 2C 2H 5, Cl and OH) at para position exhibited greater insecticidal activity against P. rapae than podophyllotoxin.

Seleno‐podophyllotoxin derivatives induce hepatoma SMMC‐7721 cell apoptosis through Bax pathway

Podophyllotoxin is a well known anti-tumor chemical, but because of its strong side effects much effort has been paid to reduce cytotoxicity by modifying its structure. Here, we evaluate the anti-tumor activity of a new isolated derivative of podophyllotoxin, 4'-demethyl-4-dehydroxy-4-seleno-phenyl-beta-peltatin-epipodophyllotoxin (CPZ) and find that CPZ can suppress the proliferation of human hepatoma SMMC-7721 cells in a dose- and time-dependent manner. Phase-contrast microscope observation and flow cytometric analysis through PI stains showed that the reagents have strong inhibition of SMMC-7721 cell growth, as the cells were blocked in the G2/M period. Cell apoptosis induced by CPZ was further confirmed by staining with M30 Cytodeath antibody. Rh123 label testing revealed that the mitochondrial membrane potential had been decreased by CPZ treatment. Under the stress of CPZ, cytochrome c was secreted into the cytoplasm by mitochondria, and Bax in cytoplasm was translocated into the mitochondrial membrane. These results suggest that CPZ-induced apoptosis may work through a Bax-dependent pathway.

Design, Synthesis and Cytotoxicity of Novel Podophyllotoxin Derivatives

A series of novel podophyllotoxin derivatives were designed using association strategy and synthesized by coupling either podophyllotoxin (1) or 4beta-amino podophyllotoxin (3) with substituted indol-3-yl-glyoxyl chlorides. Their structures were identified using spectroscopic techniques. These novel derivatives have been evaluated for cytotoxicity in vitro against four human cancer cell lines with comparison to the parent compounds 1, 3 and indibulin (2). Some of the compounds (7a, 7c) showed comparable cytotoxicity to that of podophyllotoxin.

Production of lignans in callus culture of <i>Podophyllum hexandrum</i>

Purpose: Podophyllum hexandrum Royle, a source of highly valued podophyllotoxin has been subjected to heavy collection from the wild. The ever-increasing demand of podophyllum is mainly due to two semi synthetic derivatives of podophyllotoxin that is etoposide and teniposide, which are used in the treatment of various types of cancer. The anti cancer lignan derivative podophyllotoxin in Podophyllum hexandrum is biosynthesized at very low quantities in intact plant, so the biotechnological production of podophyllotoxin has been considered essential. Method: The aseptically germinated embryos of Podophyllum hexandrum were developed on solid nutrient agar slab. For the growth of callus culture, Murashigae and Skoog media (MS media)) with various concentrations of BAP, NAA and GA3 adjusted to pH 5.8 was used. Podophyllotoxin content in the alcoholic extract of calli and plant root was analysed by HPLC and HPTLC and was also compared with cultivated Podophllum hexandrum root extracts. Result: A fully defined MS medium supplemented with Naphthalene acetic acid and 6benzylaminopurine (BAP) were effective for both initiation and sustained growth of callus tissue. The relative proportion of callus was markedly influenced by presence of plant growth regulators. The amount of Podophyllotoxin obtained from callus was 0.78 and 0.79 percent as characterized by HPLC and HPTLC respectively. Conclusion: The study revealed that callus culture may be a fruitful tool for the production of Podophyllotoxin resin, an anticancer entity.

Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin

Podophyllotoxin and related analogs present numerous challenges associated with optimal antitumor activity and severe unpredictable toxicity. In the course of our ongoing investigation of quantitative structure–activity relationships to find biorational antitumor drugs, two series of pyridine acid ester derivatives of podophyllotoxin and 4′-demethylepipodophyllotoxin have been prepared by reacting the corresponding pyridine acids with the hydroxyl group of podophyllotoxin and 4′-demethyl epipodophyllotoxin in the presence of dimethylaminopyridine (DMAP) and N,N-dicyclohexylcarbodiimde (DCC). The structures of the compounds were extensively characterized by using 1H-nuclear magnetic resonance, mass spectroscopy, infrared, and elemental analysis and evaluated for their in vitro cytotoxicity on two neoplastic cell lines (P-388 murine leukemia, A-549 human lung carcinoma) using a MTT-based assay, the results indicated significantly higher efficacy of these compounds in comparison with the prototypical inhibitor etoposide. On the basis of the preliminary biological testing results, it suggested that the cytotoxic activity of OCH3 at C-4′ is more potent than that of its demethylated analogs and the podophyllotoxin substitution at C-4 may be optimal for synthesizing more potent cytotoxic compounds.

Advances in the Synthesis of Aryltetralin Lignan Lactones

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Synthesis, anti-fungal activity evaluation and QSAR studies on podophyllotoxin derivatives

Abstract The anti-fungal and cytotoxic activites of podophyllotoxin and seven C-4 substituted podophyllotoxin ester derivatives, viz: trans-cinnamyl, cis-cinnamyl, o-methoxy cinnamyl, dimethyl acrylyl, p-methoxy phenyl acetyl, 3,4-dimethoxy phenyl acetyl and 2,5-dimethoxy phenyl acetyl esters were evaluated on four fungi, viz: Macrophomina phaseolina, Fusarium oxysporum, Myrrothecium verrucarria and Asperigillus candidus, The podophyllotoxin derivatives were synthesised and their structures were elucidated. Quantitative structure activity relationships were developed between the activity of these compounds against the four fungi and molecular descriptors. The linear regression models developed had one to two descriptors. For all the cases the r 2 was in the range of 0.73 to 0.96, indicating good data fit and q 2 was in the range of 0.60 to 0.68, indicating that the predictive capabilities of the models were acceptable. Solvent accessible surface area (namely the partial positive solvent-accessible surface area), A log P, highest occupied molecular orbital and conformational energy were identified as important descriptors.

Design, synthesis, and biological evaluation of novel spin-labeled derivatives of podophyllotoxin as potential antineoplastic agents. Part XII¶

Five novel nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a–11e) have been prepared and their structural information on these nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a–11e) using 1HNMR spectroscopy was efficiently obtained by application of the in situ reduction of representative nitroxyl spin-labeled ester derivative of podophyllotoxin 11e with phenylhydrazine for the preparation of N-hydroxylamine 12 in the NMR tube. These novel derivatives were further evaluated for their in vitro cytotoxic activity against five neoplastic cell lines (K562, HL-60, SPCA-1, Lewis, and L-1210) using MTT assay. Most of the target compounds (except for all these compounds against SPCA-1) exhibited more pronounced cytotoxicity against several neoplastic cell lines than that of the prototypical inhibitor etoposide. ¶For part XI, see Jin, Y., Chen, S. W., and Tian, X. Bioorg. Med. Chem. 2006, 14, 3062-3068.

Synthesis and insecticidal activities of novel derivatives of podophyllotoxin

In order to find the biorational pesticides, eight novel 4β-substituted phenoxyaniline derivatives of podophyllotoxin (4a–h) have been synthesized with significant stereoselectivity and improved yields by employing the BF3 · Et2O/NaI reagent system and evaluated for insecticidal activity against Pieris rapae as well as for their antifeedant effect against fifth instar larvae of P. rapae. The results showed that all these derivatives of PPT showed delayed insecticidal activity, which is different from the traditional neurotoxic insecticides. Among them, compounds possessing a 4β-phenoxyaniline moiety substituted at para (CO2C2H5, Cl, and OH) position exhibited greater insecticidal activity against P. rapae than podophyllotoxin. Also, the antifeedant activities showed that these compounds exhibited less potency than podophyllotoxin.

Advances in the Synthesis of Aryltetralin Lignan Lactones

AbstractEtoposide and tenoposide, derivatives of the aryltetralin lignan lactone podophyllotoxin (5), are clinically important anticancer agents. The structure of podophyllotoxin includes four contiguous chiral centres contained within a stereochemically unstable trans‐fused tetrahydronaphthalene lactone skeleton. Reflecting this challenging structure and important biological role there has been long‐standing interest in developing efficient stereocontrolled syntheses of this class of natural product. This microreview summarises the key developments towards this end focussing on more recent developments both from within the authors group and elsewhere.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Synthesis and Characterization of a Novel Podophyllotoxin Derivative Containing a Cyclohexadienone Group

4β-Azido-4-demethyl-4′- O -demethyl-epipodophyllotoxin reacted with phenyliodonium diacetate in MeOH at room temperature to synthesize a novel podophyllotoxin derivative containing a cyclohexadienone group with the original configurations of C2 and C4, which are required for the antitumor activities. The component and structure of the product were confirmed using elemental analysis, high-resolution mass spectrum, 1 H and 13 C NMR spectra, and infrared spectrum. Furthermore, the fragmentation routes of the product were fully assigned with electron-impact time-of-flight mass spectrometry(EI-TOF MS), which can also be used for the structural elucidation based on the molecular ion at m/z 455(16%) and three novel characteristic fragment ions at m/z 183(37%), 425(7%), and 199(5%). The cyclohexadienone product is sensitive to acidic media. When it is treated with a trace of acid, another novel derivative containing an orthoquinone moiety is formed, which links with the metabolism of the cancer inhibitors.

GP7 induces internucleosomal DNA fragmentation independent of caspase activation and DNA fragmentation factor in NB4 cells

DNA fragmentation into internucleosomal fragments is the best recognized biochemical event of apoptosis. Two major caspase pathways have been identified in the signal transduction leading to DNA fragmentation: the receptor pathway and the mitochondrial pathway. DNA fragmentation factor (DFF) has been identified as a major apoptotic endonuclease in the internucleosomal DNA fragmentation process. However, the potential roles of caspases and DFF in internucleosomal DNA fragmentation induced by specific stimuli still need to be investigated since caspase-independent pathways and nuclease(s) other than DFF also play important roles during this process. In the present study, we investigated the activity of GP7 (4-[4"-(2",2",6",6"-tetramethyl-l"-piperidinyloxy) amino]-4'-demethyl epipodophyllotoxin), a new spin-labeled derivative of podophyllotoxin semi-synthesized by our university, to induce apoptosis of the human leukemia cell line NB4. GP7 induced the release of cytochrome-c from mitochondria, activations of caspase-3, -8, and -9, cleavage of DFF45/inhibitor of caspase-activated DNase, activation of DFF40/caspase-activated DNase, and apoptotic DNA fragmentation in NB4 cells. The broad-spectrum caspase inhibitor zVAD-fmk abrogated GP7-induced caspase-3, -8, and -9 activations but could not inhibit GP7-induced apoptotic DNA fragmentation in NB4 cells. Our findings suggest that GP7-induced apoptotic DNA fragmentation in NB4 cells is independent of caspase activation and DFF, although they are closely involved in this process.

Synthesis and insecticidal activities of pyridine ring derivatives of podophyllotoxin

In an attempt to find the biorational pesticides, we synthesized 12 pyridinyl derivatives of podophyllotoxin (PPT) and 4′-demthylepipodophylltoxin (4′-DMEP) in this study. Their structures and the α/β substitution at C-4 were confirmed by 1H NMR, IR, MS spectral analyses and elemental analysis. The insecticidal activities were tested against fifth-instar larvae of Pieris rapae and the third-instar larvae of Cullex pipiens pallens at concentrations of 250 and 10 μg ml −1. Four derivatives of PPT, 4.1, 4.2, 4.3 and 4.5, showed higher insecticidal activities against P. rapae than PPT, while three derivatives of PPT, 4.4, 4.5 and 4.6, displayed higher mosquito larvicidal activity than PPT, with LC 50 values of 1.66, 3.96 and 1.54 mg l −1, respectively. Interestingly, we also found that the pyridine ring derivatives of PPT showed delayed insecticidal activity, which is different from traditional neurotic insecticides. The results suggest that 4′-OCH 3 in the PPT derivatives is essential to keep the insecticidal activity and the insecticidal activities of pyridine ring derivatives of PPT are higher than that of the derivatives of 4′-DMEP, supporting PPT has the potential to be a lead structure of semi-synthetic insecticides.

Synthesis and cytotoxic evaluation of C-9 oxidized podophyllotoxin derivatives

A series of podophyllotoxin and podophyllic aldehyde derivatives, lacking the lactone ring and oxidized at C-9 position, has been prepared. The functionalities considered at C-9 were carboxylic acids and several derivatives such as esters, amides, nitriles or anhydrides. The synthesized compounds were cytotoxic at the micromolar level, though less potent and selective than the parent compounds, revealing the influence of the C-9 electrophilic character on the potency and selectivity of these cyclolignans.

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.

The absolute configuration of a nitroxide spin labeled derivative of podophyllotoxin determined by the crystal structure

The crystal structure of the nitroxide spin labeled derivative of podophyllotoxin was first reported. X-ray analysis demonstrated that four contiguous chiral centers in the molecule, C1, C2, C3, and C4, adopt cis- (1:2), trans- (2:3), and cis- (3:4) arrangement.Key words: crystal structure, synthesis, nitroxyl radical, podophyllotoxin.

Synthesis and biological evaluation of new spin-labeled derivatives of podophyllotoxin

In order to find compounds with superior bioactivity and less toxicity, a series of spin-labeled podophyllotoxin derivatives were synthesized and tested for the partition coefficients and cytotoxicity against P-388 and A-549. Furthermore, we also determined antioxidant activities of target molecular in tissues of SD rats by the TBA method. Results revealed that most synthesized compounds showed more significant cytotoxicity against P-388 and A-549 in vitro than VP-16. Among them, 9d exhibited most potent cytotoxicity against P-388 and A-549 cells (IC 50 is <0.01 and 0.13 μM, respectively). Also, the antioxidative activities showed that the modified compounds of 4′-demethylepipodophyllotoxin ( 9a– d and 10a– c) are higher than those of podophyllotoxin series ( 8a– d). The relationship between the cytotoxity and antioxidative activity discussed.

Camptothecin and Podophyllotoxin Derivatives

Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-soluble salt camptothecin-sodium - introduced in early trials in the 1960s - was highly toxic in animals, whereas the semisynthetic derivatives irinotecan and topotecan did not cause haemorrhagic cystitis because of their higher physicochemical stability and solubility at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert's syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhoea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitising solubilisers. Leukopenia and thrombocytopenia occur in 65% and 80%, respectively, of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhoea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clinical pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concentration-time curve values and steady-state concentrations for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metabolism may be associated with a higher risk for secondary malignancies.