Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and .alpha.-peltatin

Thurston, Lee S.; Imakura, Yasuhiro; Matsushita, Haruna; Li, De Hua; Liu, Zong Chao; Liu, Su Ying; Cheng, Yung Chi; Lee, Kuo Hsiung̀

doi:10.1021/jm00123a016

Cited by 41 publications

(10 citation statements)

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“…In the same way, the activity of benzyl-[1-3]-benzodioxolic derivatives, which only slightly block tubulin, is increased when these compounds have that substituent [230]. These results suggest -Position 7 is very important in the observed antimitotic activity [120,151,217]. The free hydroxyl group at 7 contributes to the that the trimethoxyphenyl radical is able to favour the binding of the compound to the pharmacological receptor.…”

Section: Structure-antineoplastic Activity Relationshipmentioning

confidence: 93%

“…Thus, etoposide and teniposide are potent derivatives used in clinical practice whose glycosylated moiety is essential for their action, unlike what was formerly believed [218]: the derivatives with ether or ester groups at that position are generally less active [120].…”

Section: A-ring Modificationsmentioning

confidence: 98%

“…Functionalisation of position 2 leads to peltatin derivatives with a very reduced inhibitory capacity against DNAtopoisomerase II [120].…”

Section: Structure-antineoplastic Activity Relationshipmentioning

confidence: 99%

“…Regarding cytotoxicity, potency increases in the esters and ethers while glycosylated derivatives are less active [120].…”

Section: Structure-antineoplastic Activity Relationshipmentioning

confidence: 99%

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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: Structure-antineoplastic Activity Relationshipmentioning

confidence: 93%

Section: A-ring Modificationsmentioning

confidence: 98%

“…Functionalisation of position 2 leads to peltatin derivatives with a very reduced inhibitory capacity against DNAtopoisomerase II [120].…”

Section: Structure-antineoplastic Activity Relationshipmentioning

confidence: 99%

“…Regarding cytotoxicity, potency increases in the esters and ethers while glycosylated derivatives are less active [120].…”

Section: Structure-antineoplastic Activity Relationshipmentioning

confidence: 99%

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Antitumor Properties of Podophyllotoxin and Related Compounds

Gordaliza¹,

Ma²,

Jm³

et al. 2000

CPD

255

143

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“…However, some compounds (e.g., " IDeo was the concentration of drug which affords 50% reduction in cell number after a 3-day incubation. 6 Each compound was examined with five concentrations at 5,10,25,50, and 100 µ . The IDeo value was established based on the degree of inhibition at these five concentrations.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

Antitumor Agents. 148. Synthesis and Biological Evaluation of Novel 4.beta.-Amino Derivatives of Etoposide with Better Pharmacological Profiles

et al. 1994

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A series of novel 4 beta-amino derivatives of etoposide (1), which can form water-soluble salts and demonstrate excellent activity against mdr- and topo II-resistant cell lines, have been synthesized. Compared with etoposide, compounds 5-6, 8, and 10-16 show comparable or greater inhibition of human DNA topo II. In a cellular protein-DNA complex formation assay, compounds 5-6, 8, 10-14, and 16 are more potent than 1. A dose-response study of 8 shows that it is 20 times more active in formation of protein-linked DNA breaks than etoposide. Furthermore, both 8 and its free base 7 were found to be highly active toward etoposide-resistant KB cell lines. All compounds were also evaluated in vitro against a total of 56 human tumor cell lines derived from seven cancer types. Comparison of the log10 GI50 mean graph midpoints of 5-19 (-4.89 to -7.30) with that of 1 (-4.08) shows these new analogs to be 6-1659-fold more active than 1.

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Biologically Active Thiophene Derivatives Revisited: 1983–1988

Press¹

1991

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and .alpha.-peltatin

Cited by 41 publications

References 1 publication

Antitumor Properties of Podophyllotoxin and Related Compounds

Antitumor Properties of Podophyllotoxin and Related Compounds

Antitumor Agents. 148. Synthesis and Biological Evaluation of Novel 4.beta.-Amino Derivatives of Etoposide with Better Pharmacological Profiles

Biologically Active Thiophene Derivatives Revisited: 1983–1988

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