Synthesis of Analogs of 2-Methoxyestradiol with Enhanced Inhibitory Effects on Tubulin Polymerization and Cancer Cell Growth

Cushman, Mark; He, H.‐M.; Katzenellenbogen, John A.; Varma, Ravi K.; Hamel, Ernest; Lin, Chii M.; Ram, Siya; Sachdeva, Yesh P.

doi:10.1021/jm9700833

Cited by 85 publications

(76 citation statements)

References 46 publications

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“…The syntheses of compounds 1, 2, 4, 9 to 12, 26 (Cushman et al, 1995), 5, 18 (Cushman et al, 1997), 21, 22 (Verdier-Pinard et al, 2000), and 23 to 31 have been described previously. Compounds 3, 16, 18, 19, and 34-39 were purchased from Sigma (St. Louis, MO).…”

Section: Compoundsmentioning

confidence: 99%

“…Synthesis of 17␤-Acetoxy-2-ethoxy-3-hydroxy-6-hydroximinoestra-1,3,5(10)-triene (8). A solution of compound 43 (Cushman et al, 1997) (800 mg, 1.93 mmol) in pyridine (12 ml) was treated with hydroxylamine hydrochloride (1.07 g, 15.4 mmol). The resulting mixture was stirred and heated at 100°C for 30 min.…”

Section: Synthesis Of 2-formylestradiol (42)mentioning

confidence: 99%

“…Prior work has demonstrated that the cytotoxicities and tubulin polymerization inhibitory potencies of 2-MEO analogs can be modulated by replacement of the 2-methoxyl group by other substituents (Cushman et al, 1995(Cushman et al, , 1997. Replacement of the 2-methoxyl group of 2-MEO by 2-ethoxyl and 2-(E)-1-propenyl substituents resulted in compounds that were more potent than estradiol itself (Cushman et al, 1995).…”

Section: Synthetic Chemistrymentioning

confidence: 99%

“…Inhibition of smooth muscle proliferation by 2-MEO has given rise to suggestions that this or related compounds may have therapeutic applications in atherosclerosis (Nishigaki et al, 1995) and asthma (Stewart et al, 1999b), whereas regulatory effects of 2-MEO on lymphocytes and leukocytes provide a case for its use to treat rheumatoid arthritis (Jo-sefsson and Tarkowski, 1997). Furthermore, cytotoxic and antiangiogenic actions of 2-MEO on various tumor cell lines indicate that this agent has potential as an antitumor agent (Lottering et al, 1992;Fotsis et al, 1994;Cushman et al, 1995;Hamel et al, 1996;Cushman et al, 1997).…”

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confidence: 99%

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2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

et al. 2002

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2-Methoxyestradiol (2-MEO), a metabolite of estrogen, is an attractive lead compound for the development of novel antitumor and anti-inflammatory agents, because it embodies antiproliferative and antiangiogenic activities in one molecule. However, the affinity of 2-MEO for the estrogen receptor would lead to undesirable side effects. As a prelude to the design of 2-MEO-like compounds with an optimal activity profile, we assayed 2-MEO and a series of analogs for their ability to cause G 1 cell-cycle arrest (by measuring inhibition of DNA synthesis in human cultured airway smooth muscle) and to inhibit binding of [ 3 H]estradiol at the estrogen receptor (ER; from rat uterine smooth muscle). One compound, a diacetoxy enediol derivative, was identified with reasonable potency for DNA synthesis (pIC 50 ϭ 5.97) but showed negligible affinity for the ER (pIC 50 Ͻ 5). Three-dimensional quantitative structure-activity relationships were developed for these activities using comparative molecular field analysis (CoMFA) techniques. Comparison of optimized CoMFA models revealed distinct structural requirements for DNA synthesis inhibition and ER binding. For example, DNA synthesis inhibition is enhanced by electropositive substitutions in the 2-position below the plane of the steroid A-ring, whereas ER binding is favored by electronegative substitution in this position. Similarly, DNA synthesis inhibition correlates negatively with increased steric bulk in regions clustered around the A and B rings; changes in steric bulk in these regions has little correlation with ER binding. These observations will guide the design of new analogs with improved potency for desired characteristics (e.g., DNA synthesis inhibition) with minimal unwanted activities (e.g., ER binding).Interest in the metabolites of estrogen has grown in the last decade, because it has been appreciated that a number of the actions of this sex hormone may be caused by biologically active metabolites. For example, the glucuronides of estrogen and its metabolites cause cholestatic jaundice (Zhu et al., 1996), whereas the catecholestrogens are implicated in the association between estrogen and increased incidence of certain tumors (Zhu and Conney, 1998). The cardioprotective effects of estrogen have been ascribed to an interaction between estrogen and the high-affinity estrogen receptor (ER); recent evidence suggests that the cardioprotective effects of estrogen are mediated largely, if not exclusively, via the ER␣ subtype (Brouchet et al., 2001;Hodgin et al., 2001). Alternative lower affinity receptors that bind estrogen have been described, but these do not seem to interact with physiological levels of estrogen, opening up the possibility that a related ligand binds and activates these receptors under physiological conditions (Eriksson et al., 1980). 2-Methoxyestradiol (2-MEO, compound 1; Table 1), once regarded as an inactive metabolite of estrogen, has been identified as an inhibitor of the proliferation of a variety of cell types and as an antiangiogen...

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Section: Compoundsmentioning

confidence: 99%

Section: Synthesis Of 2-formylestradiol (42)mentioning

confidence: 99%

Section: Synthetic Chemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

et al. 2002

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“…1, 2), has strong antiproliferative and apoptotic actions in a number of cultured cancer cell lines when it was present at pharmacologic concentrations (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Among many of the human cancer cell lines tested thus far, several human breast cancer cell lines were found to be highly sensitive to the antiproliferative actions of 2-MeO-E 2 in vitro (3,4,12). Additional studies also showed that 2-MeO-E 2 inhibited the growth of human breast cancer cells when they were transplanted into immune-suppressed mice (10).…”

Section: Introductionmentioning

confidence: 99%

Selective Insensitivity of ZR-75-1 Human Breast Cancer Cells to 2-Methoxyestradiol: Evidence for Type II 17β-Hydroxysteroid Dehydrogenase as the Underlying Cause

Liu

Lee²,

Zhu³

2005

Cancer Research

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2-Methoxyestradiol (2-MeO-E 2 ), a nonpolar endogenous metabolite of 17B-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions. Among the four human breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, and MDA-MB-435s), the ZR-75-1 cells were selectively insensitive to the antiproliferative actions of 2-MeO-E 2 , although these cells had a similar sensitivity as other cell lines to several other anticancer agents (5-fluorouracil, mitomycin C, doxorubicin, colchicine, vinorelbine, and paclitaxel). Mechanistically, this insensitivity is largely attributable to the presence of high levels of a steroid-selective metabolizing enzyme, the type II 17B-hydroxysteroid dehydrogenase (17B-HSD), in the ZR-75-1 cells, which rapidly converts 2-MeO-E 2 to the inactive 2-methoxyestrone, but this enzyme does not metabolically inactivate other nonsteroidal anticancer agents. The type II 17B-HSD-mediated conversion of 2-MeO-E 2 to 2-methoxyestrone in ZR-75-1 cells followed the first-order kinetics, with a very short half-life (f2 hours). In comparison, the T-47D, MCF-7, and MDA-MB-435s human breast cancer cells, which were highly sensitive to 2-MeO-E 2 , had very low or undetectable catalytic activity for the conversion of 2-MeO-E 2 to 2-methoxyestrone. Reverse transcription-PCR analysis of the mRNA levels of three known oxidative 17B-HSD isozymes (types II, IV, and VIII) revealed that only the type II isozyme was selectively expressed in the ZR-75-1 cells, whereas the other two isozymes were expressed in all four cell lines. Taken together, our results showed, for the first time, that the high levels of type II 17B-HSD present in ZR-75-1 cells were largely responsible for the facile conversion of 2-MeO-E 2 to 2-methoxyestrone and also for the selective insensitivity to the antiproliferative actions of 2-MeO-E 2 . (Cancer Res 2005; 65(13): 5802-11)

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Synthesis of Aryl‐ and Heteroaryl‐Trifluoroethyl Ethers: Aims, Challenges and New Methodologies

Pethő

Novàk

2018

Asian J Org Chem

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Synthesis of Analogs of 2-Methoxyestradiol with Enhanced Inhibitory Effects on Tubulin Polymerization and Cancer Cell Growth

Cited by 85 publications

References 46 publications

2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

2-Methoxyestradiol and Analogs as Novel Antiproliferative Agents: Analysis of Three-Dimensional Quantitative Structure-Activity Relationships for DNA Synthesis Inhibition and Estrogen Receptor Binding

Selective Insensitivity of ZR-75-1 Human Breast Cancer Cells to 2-Methoxyestradiol: Evidence for Type II 17β-Hydroxysteroid Dehydrogenase as the Underlying Cause

Synthesis of Aryl‐ and Heteroaryl‐Trifluoroethyl Ethers: Aims, Challenges and New Methodologies

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