A-CD Estrogens. I. Substituent Effects, Hormone Potency, and Receptor Subtype Selectivity in a New Family of Flexible Estrogenic Compounds

Wright, James S.; Shadnia, Hooman; Anderson, James M.; Durst, Tony; Asim, Muhammad; El-Salfiti, Mohamed; Choueiri, Christine; Pratt, M.A. Christine; Ruddy, Samantha C.; Lau, Rosanna; Carlson, Kathryn E.; Katzenellenbogen, John A.; O’Brien, Peter J.; Wan, Luke

doi:10.1021/jm100513m

Cited by 23 publications

(28 citation statements)

References 63 publications

(143 reference statements)

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“…WAY treatment strongly recruited the ERb on the Bcl-2 ERE in MCF-7 cells, consistent with its high affinity for this receptor. In contrast, L17 which has a lower affinity for ERb than WAY (26,27), and retains low affinity for the ERa, recruited the ERa more strongly than WAY. Regardless, both ligands decreased Bcl-2 mRNA in both cell lines.…”

Section: Discussionmentioning

confidence: 90%

“…Ligand 17 (L17) was synthesized as previously described (26). Z-VAD-FMK was purchased from BD Biosciences.…”

Section: Chemicalsmentioning

confidence: 99%

“…In previous work, we have designed and synthesized new ligands that preferentially activate the ERb (26). The structure of L17 is based on the ABCD-ring structure of E2 but lacks the B ring.…”

Section: Introductionmentioning

confidence: 99%

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Preferential Estrogen Receptor β Ligands Reduce Bcl-2 Expression in Hormone-Resistant Breast Cancer Cells to Increase Autophagy

Ruddy¹,

Lau²,

Cabrita³

et al. 2014

Molecular Cancer Therapeutics

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Acquired resistance to selective estrogen receptor (ER) modulators (SERM) and downregulators (SERD) is a significant clinical problem in the treatment of estrogen (E2) receptor-positive (ER þ ) breast cancers. There are two ER subtypes, ERa and ERb, which promote and inhibit breast cancer cell proliferation, respectively. Although ER þ breast cancers typically express a high ratio of ERa to ERb, the acquisition of SERM resistance in vitro and in vivo is associated with increased relative expression of the ERb. On some gene enhancers, ERb has been shown to function in opposition to the ERa in the presence of E2. Here, we demonstrate that two different ERb agonists, WAY-20070 and a novel "A-CD" estrogen called L17, produce a marked reduction in G 2 -M phase correlated with effects on cyclin D1 and cyclin E expression in a SERM/SERD-resistant breast cancer cell line. ERb agonists recruited both the ERa and ERb to the Bcl-2 E2-response element strongly reducing Bcl-2 mRNA and protein in an ERb-dependent manner. L17 recruited RIP140 to the Bcl-2 promoter in cells overexpressing ERb. Exposure to the ERb ligands also resulted in increased processing of LC3-I to LC3-II, indicative of enhanced autophagic flux. The coaddition of ERb agonist and the autophagy inhibitor chloroquine resulted in a significant accumulation of sub-G 1 DNA which was completely prevented by the addition of the caspase inhibitor Z-VAD-FMK. We propose that combined therapies with an ERb agonist and an inhibitor of autophagy may provide the basis for a novel approach to the treatment of SERM/SERD-resistant breast cancers. Mol Cancer Ther; 13(7); 1882-93. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 90%

“…Ligand 17 (L17) was synthesized as previously described (26). Z-VAD-FMK was purchased from BD Biosciences.…”

Section: Chemicalsmentioning

confidence: 99%

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Preferential Estrogen Receptor β Ligands Reduce Bcl-2 Expression in Hormone-Resistant Breast Cancer Cells to Increase Autophagy

Ruddy¹,

Lau²,

Cabrita³

et al. 2014

Molecular Cancer Therapeutics

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“…31,32 Several novel SERMs have been synthesized and evaluated for their potential to improve breast cancer treatment with reduced adverse effect profile compared to the gold-standard TAM. [33][34][35] Collectively, the results of these studies demonstrate that the CYP2D6-generated 4-OH metabolites of TAM represent a much higher percentage of total plasma exposure with TAM treatment, and at many-fold greater estrogenic and antiestrogenic activity, these active TAM metabolites are likely to measurably contribute to the clinical efficacy and safety profile of TAM in women with breast cancer. Adjusted for dose, the plasma concentrations of TOR and metabolites reported in our study are consistent with the values for the 60 mg clinical dose reported in previous studies.…”

mentioning

confidence: 84%

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

Kim

Coss

Barrett

et al. 2012

Intl Journal of Cancer

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We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35-to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.Tamoxifen (TAM) is the most widely used hormone therapy for breast cancer. Toremifene (TOR), a chlorinated derivative of TAM, is also an approved treatment for metastatic breast cancer in postmenopausal women.1,2 Although TAM is the prototypical drug in the selective estrogen receptor modulator (SERM) class, its clinical efficacy and safety are known to vary widely among individuals.3 TOR is equally effective in breast cancer treatment.4-7 However, TOR may have reduced genotoxicity and lower potential to induce secondary endometrial cancers 8,9 and may therefore be considered as an alternative to TAM as firstline therapy for patients with ER-positive advanced breast cancer.TAM is extensively metabolized. The clinical benefit of TAM is thought to arise from its conversion to active metabolites, chiefly 4-hydroxy TAM (4-OH TAM) and 4-OH-N-desmethyl TAM (4-OH-NDM TAM, otherwise known as endoxifen; Fig. 1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. 13-16Whether these metabolites are responsible for TAM's variable clinical efficacy is a topic of considerable controversy. TAM is known to be metabolized extensively by the cytochrome P450 (CYP) enzyme system, primarily by the CYP3A4 and 2D6 isoforms. 17 CYP3A4 generates the major circulating metabolite mono-NDM TAM 18; however, the formation of the active TAM metabolites apparently requires cytochrome P-450 2D6 (CYP2D6).19 CY...

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“…In a subsequent account [32], Wicha showed that acylation with Ac2O of 55 along with selective removal of the less Terpene and terpenoid derivatives are well known to hold significant bioactivity, thus it should be no surprise that the bicyclo[4.3.0]nonane scaffold should also possess some selectivity relevant for medical applications. Indeed, this is true, and more surprisingly, selectivity in some cases is driven by substitution of the hydrindane [10,11,26,27]. Progesterone analogues were discovered to inhibit angiogenesis in conjunction with heparin (see Scheme 7) [11].…”

Section: Hajos-parrish Dionementioning

confidence: 99%

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

Eddy

Ichalkaranje

2016

Molecules

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Abstract:The bicyclo[4.3.0]nonane scaffold, commonly known as a hydrindane, is a common structural motif found in many terpenoid structures and one that remains a challenge for synthetic chemists to elaborate with appropriate regio-and stereo-selectivity. Over the course of the study of terpene natural products, the elaboration of the hydrindane structure has seen progress on the utilization of both old and newer methods to achieve the desired outcomes. This review seeks to serve as a general overview of these methods, and detail specific examples.

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A-CD Estrogens. I. Substituent Effects, Hormone Potency, and Receptor Subtype Selectivity in a New Family of Flexible Estrogenic Compounds

Cited by 23 publications

References 63 publications

Preferential Estrogen Receptor β Ligands Reduce Bcl-2 Expression in Hormone-Resistant Breast Cancer Cells to Increase Autophagy

Preferential Estrogen Receptor β Ligands Reduce Bcl-2 Expression in Hormone-Resistant Breast Cancer Cells to Increase Autophagy

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

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