A Review on Hemisynthesis, Biosynthesis, Biological Activities, Mode of Action, and Structure-Activity Relationship of Podophyllotoxins: 2003- 2007

徐, 会連; Lv, Min; Tian, Xuan

doi:10.2174/092986709787002682

Cited by 187 publications

(76 citation statements)

References 69 publications

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“…One of these sources is the rhizomes of the plant Podophyllum peltatum [6]. Due to a combination of the slow growth-rate of the plant and increasing demand for PPT [7][8][9], various other approaches for the chemical synthesis and in vitro production of PPT have been explored [1,[10][11][12][13][14]. These methods have so far proven to be inadequate for the commercial production of PPT due to low yields and high costs.…”

Section: Introductionmentioning

confidence: 99%

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Arneaud

Porter

2015

Mol Biotechnol

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Podophyllotoxin (PPT) is a plant natural product that serves as a precursor for the synthesis of many well-known chemotherapeutic drugs. The limited availability and high demand for the source plants of PPT have led to the exploration of alternative sources for this compound. In this study, we utilized the endophytic fungus Phialocephala podophylli (strain PPE7) that we isolated from the rhizomes of Podophyllum peltatum and is known to produce detectable amounts of PPT in broth culture. To date, the complete PPT biosynthetic pathway has yet to be determined in any species. Since fungi are well known for clustering genes that belong to secondary metabolite pathways, use of a fungal system for investigation of the PPT biosynthesis genes may ultimately lead to elucidation of the entire pathway. In this study, we investigated the secoisolariciresinol dehydrogenase (SD) gene that facilitates the dehydrogenation of secoisolariciresinol to form matairesinol, a mid-pathway intermediate product in PPT biosynthesis. We utilized PCR amplification to acquire the complete SD gene sequence in PPE7 and opted to synthesize the P. peltatum SD sequence for expression. Through western blotting, we confirmed the expression of the recombinant SD (PpSD) and verified protein functionality with a bioconversion assay followed by HPLC and LC-MS analyses. Here, we report the identification of the SD gene in PPE7; this is the first report of the SD gene in an endophytic fungus. Additionally, we established the groundwork for the future expression of the complete PPT biosynthetic pathway in the heterologous host Pichia pastoris.

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Section: Introductionmentioning

confidence: 99%

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Arneaud

Porter

2015

Mol Biotechnol

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“…The unique cyclolignan scaffold of 1 has however drawn a lot of attention for the discovery and development of new anticancer agents. Extensive structural modifications, particularly at the C-4 and C-4' position of podophyllotoxin have led to the development of many semisynthetic derivatives of podophyllotoxin [4][5][6]. Among them, five semisynthetic derivatives, etoposide (2), teniposide (3), etopophos (4), GL-331 (5) and TOP-53 (6) ( Figure 1) are currently used in the chemotherapy for a variety of cancers, including small-cell lung cancer, non-Hodgkin's lymphoma, leukemia, Kaposi's sarcoma, neurobslastoma and soft tissue sarcoma.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

Xu²,

et al. 2013

Molecules

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A series of 4β-triazole-linked glucose podophyllotoxin conjugates have been designed and synthesized by employing a click chemistry approach. All the compounds were evaluated for their anticancer activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Most of these triazole derivatives have good anticancer activity. Among them, compound 35 showed the highest potency against all five cancer cell lines tested, with IC 50 values ranging from 0.59 to 2.90 μM, which is significantly more active than the drug etoposide currently in clinical use. Structure-activity relationship analysis reveals that the acyl substitution on the glucose residue, the length of oligoethylene glycol linker, and the 4'-demethylation of podophyllotoxin scaffold can significantly affect the potency of the anticancer activity. Most notably, derivatives with a perbutyrylated glucose residue show much higher activity than their counterparts with either a free glucose or a peracetylated glucose residue.

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“…Colchicine site binding agents are traditionally believed to need a biaryl structure, limited conformational mobility, and a trimethoxyphenyl group to effectively bind this site (Xu et al, 2009). For purposes of this discussion, the rings of podophyllotoxin will be labeled from left to right (Fig.…”

Section: Discussionmentioning

confidence: 99%

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

et al. 2011

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Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G 2 /M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC 50 of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the ␤III isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents.

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A Review on Hemisynthesis, Biosynthesis, Biological Activities, Mode of Action, and Structure-Activity Relationship of Podophyllotoxins: 2003- 2007

Cited by 187 publications

References 69 publications

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

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