Components of Podophyllin. V. The Constitution of Podophyllotoxin<sup>1</sup>

Hartwell, Jonathan L.; Schrecker, Anthony W.

doi:10.1021/ja01150a143

Cited by 112 publications

(24 citation statements)

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“…Podophyllotoxin 1 is a cyclolignan isolated from different plant species and is especially abundant in those of the genus Podophyllum [59], which has been used since remote times for medicinal purposes as cathartic and antihelminthic agents. Podophyllin, the alcoholic extract from the rhizomes of Podophyllum, was included in the U.S. Pharmacopoeia in 1820 and in 1942 Kaplan described the use of this resin for the treatment of venereal warts [60], attributing this action to podophyllotoxin, the major component of the resin [61].…”

Section: Podophyllotoxin Etoposide and Teniposidementioning

confidence: 99%

Antitumor Properties of Podophyllotoxin and Related Compounds

Gordaliza¹,

Ma²,

Jm³

et al. 2000

CPD

255

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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Section: Podophyllotoxin Etoposide and Teniposidementioning

confidence: 99%

Antitumor Properties of Podophyllotoxin and Related Compounds

Gordaliza¹,

Ma²,

Jm³

et al. 2000

CPD

255

143

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“…Podophyllotoxin (5 g) was dissolved in absolute ethanol (100 ml) containing anhydrous sodium acetate (1 g) and refluxed overnight (8). Hot water (200 ml) was added and the solution brought to a boil.…”

Section: Synthesis Of Tritnethyl Plicatirraplttlraletre ( 3 ) Frornmentioning

confidence: 99%

Lignans of western red cedar (Thujaplicata Donn). IX. Plicatinaphthalene

MacLean¹,

MacDonald²

1969

Can. J. Chem.

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The last of nine lignans detectable by thin-layer chromatography in the hot-water soluble extractives of western red cedar (Thujaplicata Donn) heartwood has been determined as 6-hydroxy-2(hydroxy-methyl)-7-methoxy-4-(3′,4′-dihydroxy-5′-methoxyphenyl)-3-naphthoic acid lactone (plicatinaphthalene 2) by spectrometric methods, by degradation studies of derivatives, and by preparation of its trimethyl ether derivative 3 from dehydroanhydropicropodophyllin by opening of the methylenedioxy group with boron trichloride.

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“…The optical rotation of APPT indicated that this isomerization did not emerge ([α] 20 D : podophyllotoxin, −132°; picropodophyllin, +9°; acetylpodophyllotoxin, −117°; acetylpicropodophyllin, +19°; APPT, −108°.) [16,17,18,19]. C-NMR spetra of podophyllotoxin, picropodophyllin, epipodophyllotoxin and their 4-acetylate derivatives in previous reports [3,19,20,].…”

Section: Resultsmentioning

confidence: 93%

“…On the synthesis of podophyllotoxin derivatives, it was necessary to establish the configuration, because the configuration of H protons at position 2 or 4 on podophyllotoxin will possibly isomerize to that of picropodophyllin (2β -H → 2α -H) at the environment of basic capacity and to that of epipodophyllotoxin (4β -H → 4α -H) at the environment of acidic capacity [3,16,17], and the antitumor activity will possibly decrease with the change of the configuration [17]. The configuration of H protons on podophyllotoxin skeleton of APPT did not isomerize at our checked condition of synthesis (Figure 1), there are three reasons: (1) The ismoerization of the configuration of H protons on podophyllotoxin skeleton usually emerged at 60-80°C [3,16,17], but the APPT was synthesized at 0-25°C.…”

Section: Resultsmentioning

confidence: 99%

Preparation of new polymer from podophyllotoxin derivative

et al. 2001

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The new monomer, 4α-acrylpodophyllotoxin(APPT) was synthesized from reaction of acryloyl chloride with the 4α-hydroxy of podophyllotoxin. The homo-and copolymer of new monomer with NIPAAm/AAm have been prepared by free radical polymerization. The new monomer and polymers have been characterized by IR, 1 Hand 13 C-NMR spectra. The homopolymer have low the molecular weight but it is not oligomer, and the molecular weight of copolymer increased with decreasing new monomer content. The composition of copolymers was close to the original monomer composition. The distinction of antitumor activity among podophyllotoxin, new monomer and homopolymer was smaller. The copolymer with NIPAAm (The PAPPT content (mol-%) =43.7%) did not exhibit any antitumor activity at present condition of experimentation.

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Components of Podophyllin. V. The Constitution of Podophyllotoxin¹

Cited by 112 publications

References 0 publications

Antitumor Properties of Podophyllotoxin and Related Compounds

Antitumor Properties of Podophyllotoxin and Related Compounds

Lignans of western red cedar (Thujaplicata Donn). IX. Plicatinaphthalene

Preparation of new polymer from podophyllotoxin derivative

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Components of Podophyllin. V. The Constitution of Podophyllotoxin1

Cited by 112 publications

References 0 publications

Antitumor Properties of Podophyllotoxin and Related Compounds

Antitumor Properties of Podophyllotoxin and Related Compounds

Lignans of western red cedar (Thujaplicata Donn). IX. Plicatinaphthalene

Preparation of new polymer from podophyllotoxin derivative

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Components of Podophyllin. V. The Constitution of Podophyllotoxin¹