Synthesis and Antitumor Activity of New Glycosides of Epipodophyllotoxin, Analogues of Etoposide, and NK 611

Daley, Laurent; Guminski, Yves; Demerseman, P.; Kruczynski, Anna; Etiévant, Chantal; Imbert, Thierry; Hill, Bridget T.; Monneret, Claude

doi:10.1021/jm9800752

Cited by 39 publications

(23 citation statements)

References 42 publications

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“…In the meantime, some of the nonsugar substituted analogs of PPT, particularly the C(4 )-N-substituted congeners of PPT, such as GL-331 (7) and NPF (8) more active than VP-16 in their inhibition of the human DNA topo II [33][34][35][36][37]. Therefore, a number of 4-substituted derivatives of PPT were synthesized and tested on human topo II inhibitory or cytotoxic activity, and some compounds showed moderate to good activity against the tested cell lines [14].…”

Section: C-ring Modifications and Sarmentioning

confidence: 99%

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

徐¹,

Lv²,

Tian³

2009

CMC

185

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Podophyllotoxin is an important and much sought after antimitotic natural lead compound, since it paved the way for three hemisynthetic derivatives of podophyllotoxin, e.g., etoposide, teniposide and etopophos, which are widely used as anticancer drugs and show good clinical effects against several types of neoplasms. Although the publication of the recent reviews by Gordaliza in 2004 and You in 2005, which covered the literatures concerning podophyllotoxin until the early part of 2003, there have been significant number of works carried out on podophyllotoxin recently. Therefore, this review presents up-to-date coverage of podophyllotoxin in regard to hemisynthesis, biosynthesis, biological activities, mode of action and structure-activity relationship.

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Section: C-ring Modifications and Sarmentioning

confidence: 99%

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

徐¹,

Lv²,

Tian³

2009

CMC

185

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“…The high selectivity of TOP-53 has been attributed to its distribution into the lung and its persistance. Modification in the sugar ring resulted in the development of the agent NK-611 which is currently undergoing clinical trials [90,196,207,208], Fig. (4).…”

Section: Numbering Systems For the Cyclolignansmentioning

confidence: 99%

“…The literature reports a high number of derivatives of podophyllotoxin, substituted at 7, many of them more potent than the cyclolignans already introduced into clinical practice and also others with similar activities [20,90,182,195,206,208,[219][220][221][222][223][224][225][226][227][228].…”

Section: Structure-antineoplastic Activity Relationshipmentioning

confidence: 99%

Antitumor Properties of Podophyllotoxin and Related Compounds

Gordaliza¹,

Ma²,

Jm³

et al. 2000

CPD

252

143

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The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.

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“…There is a growing interest in exploiting lignans, and their synthetic derivatives, as potential anti-cancer agents [1], [2]. Indeed, some cytotoxic lignan derivatives have reached phase I and II clinical trials as anti-tumor agents including GP-11 [3], NK-611 [4], [5], TOP-53 [6], NPF [7], GL-331 [8]–[12]. More recently, the lignan F11782 was shown to be a novel catalytic inhibitor of topoisomerases I and II, key promoters of DNA replication [13].…”

Section: Introductionmentioning

confidence: 99%

Evaluation and Structure-Activity Relationship Analysis of a New Series of Arylnaphthalene lignans as Potential Anti-Tumor Agents

Luo

Kong

et al. 2014

PLoS ONE

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Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6′-hydroxy justicidin A (HJA), 6′-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6′ significantly increased the antiproliferative activity of arylnaphthalene lignans while a methoxyl at C-1 significantly decreased the effect.

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Synthesis and Antitumor Activity of New Glycosides of Epipodophyllotoxin, Analogues of Etoposide, and NK 611

Cited by 39 publications

References 42 publications

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

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

Antitumor Properties of Podophyllotoxin and Related Compounds

Evaluation and Structure-Activity Relationship Analysis of a New Series of Arylnaphthalene lignans as Potential Anti-Tumor Agents

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