Design, synthesis, and evaluation of estradiol-linked genotoxicants as anti-cancer agents

Sharma, Uday; Marquis, Jolm C.; Dinaut, A. Nicole; Hillier, Shawn; Fedeles, Bogdan I.; Rye, Peter T.; Essigmann, John M.; Croy, Robert G.

doi:10.1016/j.bmcl.2004.04.064

Cited by 36 publications

(33 citation statements)

References 13 publications

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“…However, the absolute difference between DNA damage produced by passive diffusion (4-OHEN in ER(Ϫ) cells and menadione) versus ER-assisted active transport (4-OHEN in ER(ϩ) cells) is modest. In accord with this observation, Essigmann and colleagues (54,55) have reported that a nitrogen mustard conjugated to estrogen showed no more than a 2.5-fold higher potency toward killing ER␣(ϩ) cells. The rate of oxidative DNA damage caused by agents such as 4-OHEN and menadione is expected to be amplified by high nuclear concentrations of the redox-cycling quinones generating high local concentrations of ROS, in particular the more reactive ROS, such as hydroxyl and alkoxyl radicals.…”

Section: Discussionmentioning

confidence: 88%

Estrogen Receptor α Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus

Wang

Wijewickrama

Peng

et al. 2009

Journal of Biological Chemistry

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Exposure to estrogens increases the risk of breast and endometrial cancer. It is proposed that the estrogen receptor (ER) may contribute to estrogen carcinogenesis by transduction of the hormonal signal and as a "Trojan horse" concentrating genotoxic estrogen metabolites in the nucleus to complex with DNA, enhancing DNA damage. 4-Hydroxyequilenin (4-OHEN), the major catechol metabolite of equine estrogens present in estrogen replacement formulations, autoxidizes to a redox-cycling quinone that has been shown to cause DNA damage. 4-OHEN was found to be an estrogen of nanomolar potency in cell culture using a luciferase reporter assay and, using a chromatin immunoprecipitation assay, was found to activate ER␣ binding to estrogen-responsive genes in MCF-7 cells. DNA damage was measured in cells by comparing ER␣(؉) versus ER␣(؊) cells and 4-OHEN versus menadione, a reactive oxygen species (ROS)-generating, but non-estrogenic, quinone. 4-OHEN selectively induced DNA damage in ER␣(؉) cells, whereas menadione-induced damage was not dependent on cellular ER status. The rate of 4-OHEN-induced DNA damage was significantly enhanced in ER␣(؉) cells, whereas ER status had no effect on the rate of menadione-induced damage. Imaging of ROS induced by 4-OHEN showed accumulation selective for the nucleus of ER␣(؉) cells within 5 min, whereas in ER␣(؊) or menadione-treated cells, no selectivity was observed. These data support ER␣ acting as a Trojan horse concentrating 4-OHEN in the nucleus to accelerate the rate of ROS generation and thereby amplify DNA damage. The Trojan horse mechanism may be of general importance beyond estrogen genotoxins.An increased relative risk of breast cancer in postmenopausal women is strongly linked to several endocrine-related risk factors. One of these risk factors is long-term exposure to hormone or estrogen replacement therapy (HRT 3 or ERT). The most widely prescribed formulations in the United States contain conjugated human estrogens and B-ring unsaturated conjugated equine estrogens, the latter constituting approximately half of the estrogen content of these formulations (1). Observations from various clinical trials and epidemiological studies collectively support the hypothesis that estrogen contributes to breast cancer and is probably causative (2-8). The large prospective Women's Health Initiative Study comparing postmenopausal women assigned HRT/ERT or placebo was terminated because of significant increases in breast cancer, stroke, and pulmonary embolism associated with therapy (9, 10). A recent analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries showed that the age-adjusted incidence rate of breast cancer fell 6.7% in 2003 compared with 2002, which was linked to lowered use of HRT/ERT (11). The collective evidence supports contributions to estrogensensitive breast cancer from both the proliferative and antiapoptotic hormonal effects of estrogen itself (12-16) and the genotoxic and mutagenic effects of estrogen metabolites (...

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Section: Discussionmentioning

confidence: 88%

Estrogen Receptor α Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus

Wang

Wijewickrama

Peng

et al. 2009

Journal of Biological Chemistry

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“…Estramustine [41][42][43][44] is a typical example of this category of compounds that has been found to also act through the disruption of interphase and mitotic microtubule network in cells, thus achieving cell death. Moreover, recent studies have shown that hormone-linked genotoxicants have the ability to interact with tumor-specific proteins and block their action, whereas at the same time the drug-protein complex formed camouflages the DNA adducts from being repaired by excision repair enzymes [21][22][23].…”

Section: Resultsmentioning

confidence: 99%

“…Apparently the effectiveness of these molecules involves the existence of other mechanisms of actions as a number of recent studies have revealed. Indications for a relative enrichment of DNA-damaging effects in the tumor tissue and for reduced myelotoxicity have been obtained with specific hormone conjugates [21,22], whereas in a recent study a rationally designed hormone-linked genotoxicant was found to possess the ability to block repairing enzymes by camouflaging the DNA-adducts formed [23].…”

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confidence: 99%

Structure–antileukemic activity relationship study of B- and D-ring modified and nonmodified steroidal esters of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid: a comparative study

et al. 2007

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This study was designed as a rational continuation of our research regarding the functional requirements essential for the antileukemic activity of compounds comprising an alkylating moiety and a modified steroid. The steroidal esteric derivatives of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid were tested on leukemias P388 and L1210 in vivo and in normal human lymphocytes in vitro. Among them the B-lactamic steroidal esters proved more potent antileukemic agents than the 7-oxidized and those with a simple B-ring, but not more effective inducers of DNA damage and cell cycle arrest in vitro. We speculate that these results indicate a different mechanism of action induced by the lactamized B steroidal ring, in comparison to the 7-keto or the D-lactamic groups, which involves the interaction of the -NHCO- moiety with cellularcomponents essential for tumor growth. 4-Methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid proved a more proper module for the B-lactams than chlorambucil and phenyl acetic acid's nitrogen mustard probably because the esteric bond is less cleaved by the esterases, resulting in an increased concentration of the drug in the vinicity of the target site essential for an antineoplasmatic response.

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“…32,33 Control studies using mitomycin C indicated that it is marginally more potent in the MCF-7 vs. the MDA-231 cell lines. Incorporation of the anti-estrogen moiety linked through the triethylene glycol to the mitomycin C in hybrid 1 had little additional effect compared to mitomycin C on the anti-proliferative response in the MCF-7 or MDA-MB-231 cells.…”

Section: Resultsmentioning

confidence: 99%

Convergent synthesis of a steroidal antiestrogen-mitomycin C hybrid using “click” chemistry

et al. 2012

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A convergent synthesis of a novel estrogen receptor-targeted drug hybrid was developed based on structures of the potent anti-proliferative mitomycin C and the steroidal anti-estrogen RU 39411. The steroidal antiestrogen was prepared with an azido-triethylene glycoloxy linker while the mitomycin C derivative (porfirimycin) incorporated a complementary 7-N-terminal alkyne. The two components were ligated using the Huisgen [3 + 2] cycloaddition (“click”) reaction. Preliminary biological assays demonstrated that the final hybrid compound retained both potent anti-estrogenic and anti-proliferative activities.

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Design, synthesis, and evaluation of estradiol-linked genotoxicants as anti-cancer agents

Cited by 36 publications

References 13 publications

Estrogen Receptor α Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus

Estrogen Receptor α Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus

Structure–antileukemic activity relationship study of B- and D-ring modified and nonmodified steroidal esters of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid: a comparative study

Convergent synthesis of a steroidal antiestrogen-mitomycin C hybrid using “click” chemistry

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