Podophyllotoxin Analogues Research Articles

Synthesis and characterization of new tetralone esters

Podophyllotoxin belongs to the cyclolignan family of natural products. It exhibits cathartic, cytotoxic, antimitotic, anticancer and other biological activities. The new tetralone esters 4, 5, 6 and 7 of podophyllotoxin analogues were synthesized in very good yields by chalcone route. They were synthesized by modifying 1,3-methylene dioxy ring A, ring C, the lactone ring D and the ring E of podophyllotoxin 1 to study structure activity relationship. All the products were characterized by spectral and elemental analysis data.

Iodine‐Promoted Oxidative Conversion of o‐Vinyl Diaryl Ketones into o‐Acetyl Diaryl Ketones, Synthesis of 1‐Methyl‐4‐arylphthalazines as Analogues of Podophyllotoxin

AbstractA new method is described for the metal‐free oxidation of o‐vinyl diaryl ketones in the presence of molecular iodine or N‐iodosuccinimide to give o‐acetyl diaryl ketones. This transformation involves the initial formation of an iodohydrin, and the o‐carbonyl group of the iodohydrin participates in a subsequent rearrangement to give the o‐acetyl diaryl ketone. The presence and participation of ortho‐carbonyl group is necessary for successful conversion. The envisaged 1‐methyl‐4‐arylphthalazines were synthesized from these o‐acetyl diaryl ketones, and their antiproliferative activity on mammalian cell lines was studied.

Design, synthesis and cytotoxic activity of novel sulfonylurea derivatives of podophyllotoxin

Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41–1.76μM) and 14e (IC50: 1.72–2.01μM) showed superior cytotoxic activity compared with etoposide (IC50: 2.03 to >20μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure–activity relationship (SAR) correlations indicated that the 4′-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin’s 4β position can significantly improve cytotoxic activity.

Synthesis and characterization of diaza analogues of podophyllotoxin

In an attempt to synthesize the novel diaza analogues of podophyllotoxin (7a-d) in five step reactions. The synthesis of title compounds has been achieved from tetralones, which were formylated with ethylformate; prepared via cyclization with hydrazine hydrate. Furthermore, these newly synthesized compounds were characterized by spectral and elemental analysis data.

Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents

Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2′ position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1–C1′ bond of 2′-chloro or 2′-bromopodophyllotoxin was restricted. When 2′-chloro or 2′-bromopodophyllotoxin reacted with N-chlorosuccinimide (NCS), the chlorine atom was regioselectively introduced at their C6′ position on the E-ring. Whereas 2′-chloro or 2′-bromopodophyllotoxin reacted with NBS, the bromine atom was regioselectively introduced at their C5 position on the B-ring. When 2′-chloropodophyllotoxin reacted with different carboxylic acids in the presence of BF3·Et2O, the steric effect of its E-ring for stereoselective synthesis of 4β-acyloxy-2′-chloropodophyllotoxin derivatives was observed. The insecticidal activity of 2′(2′,6′)-(di)halogen-substituted podophyllotoxin derivatives were evaluated with Mythimna separata Walker.

Synthesis and anti-tumor activity evaluation of novel podophyllotoxin derivatives

Abstract In order to investigate the effects on the cytotoxicity of indole-3-oxalylamino podophyllotoxin analogs, seven novel podophyllotoxin derivatives were synthesized. The compounds were tested against Hela, K562 or K562/A02 cancer cells in vitro , four of which showed significant cytotoxicity. Among them 9a , 9b and 9c were superior to the positive control VP-16.

Synthesis of new tetralone ester intermediates for podophyllotoxin analogues

Podophyllotoxin is a naturally occurring lignan compound which exhibits anticancer, anti AIDS and other biological activities. New tetralone ester intermediates of podophyllotoxin analogues were synthesised in very good yields by chalcone route. They were synthesized by replacing the 3,4,5-trimethoxy groups in podophyllotoxin respectively with hydrogen, methoxy and nitro group and also 1,3- methylene dioxy group with methyl thio group to study structure activity relationship. All the products were characterized by spectral and elemental analysis data.

Drugs that inhibit tubulin polymerization: the particular case of podophyllotoxin and analogues.

Tubulin being a major cellular target for antitumor drugs, tubulin-interacting compounds have attracted great attention as antimitotic agents. Two main classes of antimitotic drugs are known and one of them includes podophyllotoxin, a natural product. The clinical use of podophyllotoxin in the treatment of cancer has been limited by severe toxic side effects. In an attempt to find less toxic analogues, many podophyllotoxin derivatives have been prepared. Identification of two types of mechanisms of action has led to the development of two groups of podophyllotoxin analogues: tubulin polymerisation inhibitors and topoisomerase II inhibitors. The present article focuses on the first group of podophyllotoxin analogues i.e. those that retain "podophyllotoxin-like" activity. The review starts with a short summary of the structural characteristics of tubulin and its interactions with drugs that affect the microtubule dynamics and then deals with the particular case of podophyllotoxin. Particular attention is given to the nature and the location of the binding sites compared to those of colchicine. The main purpose of the present review being the search for structure-activity relationships, the structural significant features required for antitubulin activity are described and discussed in details.

Abstract A67: Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of novel N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives with halo substitutions on ring-E

Abstract Podophyllotoxin is a natural product obtained from endangered Berberidaceae family species. Derivatives namely etoposide, etopophos and teniposide have been developed from podophyllotoxin and are currently used in clinic for the treatment of a variety of malignancies since five decades. Synthesis of podophyllotoxin is not feasible so far and due to this reason structural modification of podophyllotoxin could not be explored very well. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. In past we have developed synthetic analogues of podophyllotoxin i.e. aza-podophyllotoxin derivatives an important scaffold to address this chemistry. We have developed some heterocyclic analogues of podophyllotoxin i.e. N-hydroxyethyl-4-aza-podophyllotoxin derivatives. Owing to their promising activity against 60 cell lines at NCI, we further developed a novel library of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives substituted at ring-E by halogens. This was followed by a screen of in-vivo activity using a panel of tumor hollow-grafts implanted in mice consisting of breast (MDA-MB-231), non-small lung (NCI-H23 and NCI-H522), colon (SW-620 and COLO 205), melanoma (UACC-62, MDA-MB-435 and LOXIMVI), ovarian (OVCAR-5 and OVCAR-3) and CNS (U251 and SF-295) cell lines. These new compounds shows comparatively good activity against ovarian and melanoma cancer lines. Citation Format: Ajay Kumar, Vineet Kumar, Antonio E. Alegria, Malhotra V. Sanjay. Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of novel N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives with halo substitutions on ring-E. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A67.

Synthesis and evaluation of novel podophyllotoxin analogs

Because prior studies have shown inconsistency between structure–activity relationships for podophyllotoxin derivatives as topoisomerase II inhibitors and cytotoxic agents, eight novel podophyllotoxin analogs were synthesized to further explore the effects of structural variations on both A and D rings on activity. The new compounds contain a 4,5-dimethoxy substituted A ring and opened D-ring variants and were prepared by appropriate functional and stereochemical operations at the methylenedioxy group, C7, C8, and C8′. Four compounds (15, 18, 21 and 22) demonstrated noticeable inhibitory activity against A549, DU145, KB and KBvin tumor cells, and the most active compound 18 showed IC50 values less than 10μg/mL.

Palladium(II)-catalyzed enyne cyclization strategies toward the podophyllotoxin ring system

A functionally enriched ABCD ring system of podophyllotoxin was generated through Pd(II)-templated cyclization of an alkynoic alkene, prepared in five steps from commercially available 6-bromopiperonal. This research expands upon the recent carboesterification methodology of Dong et al. ( Angew. Chem., Int. Ed. 2009, 48, 9690–9692) by the application of PdCl 2(MeCN) 2, LiCl, and CuCl 2 conditions, which yielded the desired podophyllotoxin scaffold with an embedded vinyl chloride moiety. Likewise, these conditions were successfully applied to a propargylic alkene prepared in three steps from 6-bromopiperonal. The resulting product contains the ABCD ring system of podophyllotoxin, but substitutes a D-ring furan for the D-ring lactone. Application of the recent methodology of Lu et al. ( J. Org. Chem. 1995, 60, 1160–1169) on a related 1,6-enyne substrate led to functionalized α-methylene γ-butyrolactones instead (Pd 2(dba) 3·CHCl 3, LiBr, and CuBr 2). The latter conditions applied to an alkynoic alkene afforded the ABCD ring system of podophyllotoxin with a vinyl bromide group. These vinyl halides allow for derivatization at a critical juncture in order to access novel podophyllotoxin analogs.

Synthesis and Biological Evaluation of 4α/4β‐Imidazolyl Podophyllotoxin Analogues as Antitumor Agents

A series of 4α/4β-imidazolyl podophyllotoxin analogues have been designed and synthesized. All of the compounds were evaluated for their anticancer activity against a panel of three human cancer cell lines. Within the cell lines tested, some of the synthesized compounds showed promising anticancer activity. Compound 12, in particular, exhibited remarkable cytotoxicity, demonstrating effects against all tumor cell lines, including the K562/ADM cell line.

Synthetic and application perspectives of azapodophyllotoxins: alternative scaffolds of podophyllotoxin.

Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities.

Podophyllotoxin-derived insecticidal agents: Part XIII – Evaluation of insecticidal activity of podophyllotoxin derivatives against Brontispa longissima

In an attempt to find the biorational insecticides for Brontispa longissima control, 12 podophyllotoxin (PPT) analogues were tested for their insecticidal activity against the fifth-instar larvae of B. longissima in vivo for the first time. Among all the tested compounds, especially compounds 6 and 8 showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach. The different insecticidal activity range of compounds 1–12 indicated that the variation of chemical structures in the PPT skeleton markedly affected the activity profiles of this compound class, and some important structure–activity relationship information has been revealed. Together, these preliminary results may be useful in guiding further modification of PPTs in the development of potential new insecticides.

ChemInform Abstract: Synthesis and Biological Evaluation of New 4β‐Anilino‐4′‐O‐demethyl‐4‐desoxypodophyllotoxin Derivatives as Potential Antitumor Agents.

AbstractThe title podophyllotoxin analogues are evaluated for their cytotoxicities against four human cancer cell lines including KB, KB/VCR, A549, and 95D.

4β-Isocyanopodophyllotoxins: valuable precursors for the synthesis of new podophyllotoxin analogues

AbstractA new and efficient method for the synthesis of novel 4β-isocyanopodophyllotoxins as a valuable building block for the synthesis of versatile bioactive podophyllotoxin analogues under both classical and ultrasonic conditions was developed. In general, significant improvements in rates of reaction and yields of sonochemical reactions relative to the classical ones were observed.

Inside Cover: Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular-Disrupting Agents (ChemMedChem 12/2010)

Inside Cover: Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular-Disrupting Agents (ChemMedChem 12/2010)

Evaluation of insecticidal activity of podophyllotoxin derivatives against Brontispa longissima

Twenty podophyllotoxin analogues were first tested for their insecticidal activity against the fifth-instar larvae of Brontispa longissima in vivo. Among them, compounds 6– 9 and 19 showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach. The different insecticidal activity ranges of compounds 1– 20 indicated that variation of chemical structures in the podophyllotoxin skeleton markedly affected the activity profiles of this compound class, and some important SAR information has been revealed from it. The results obtained from SAR analysis show good correlation with the docking models as well as with QSAR studies, which allows for the rational design of more potent podophyllotoxin derivatives in the development of potential new insecticides.

Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular‐Disrupting Agents

We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA-4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular-disrupting agents in the podophyllotoxin series.

Podophyllotoxin Derivatives Show Activity against Brontispa Longissima Larvae

In an attempt to find biorational insecticides, eleven podophyllotoxin analogues were tested for their insecticidal activity against the fifth-instar larvae of Brontispa longissima in vivo for the first time. Among all of the tested compounds, deoxypodophyllotoxin (3) and beta-apopicropodophyllin (4) showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia toosendan, and important SAR information has been revealed. Together, these preliminary results may be useful in guiding further modification of podophyllotoxins in the development of potential new insecticides.