Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

Miller, William R.; Bartlett, John M.S.; Brodie, Angela; Brueggemeier, Robert W.; Salle, E. Di; Lønning, Per Eystein; Llombart, Antonio; Maass, Nicolaì; Maudelondé, Thierry; Sasano, Hironobu; Goss, Paul E.

doi:10.1634/theoncologist.2008-0055

Cited by 99 publications

(82 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, this modification almost led to the retention of a comparable cytotoxic effect against the MCF-7 and MDA MB-231 cell lines displaying IC 50 s of 0.75 and 1.20 µM, slightly less than the standard ludartin with IC 50 s of 0.5 and 0.67 µM against the same cancer cell lines, respectively. Among all of the compounds, the parent ludartin (3) and its 1,10-epoxy analog (11) were the most active because of the intact α-methylene-γ-lactone moiety and that the reductive amination at this moiety leads to analogs with a reduced cytotoxic effect, but enhances the cell line selectivity, which was evident from our previous studies as well [7,8]. Surprisingly, the dimethyl amino analogs (12 and 18) of 1,10-epoxy ludartin (11) and ludartin (3) were inactive against all of the cancer cell lines.…”

mentioning

confidence: 70%

“…Among all of the synthesized compounds, only one compound, namely, (11R)-13-[1-(3,4-dimethylphenyl) [1-3] triazol-4-ylmethylamine]-11R,13-dihydroludartin, displayed a potent effect with an IC 50 of 8.5 µM and the parent ludartin molecule displayed an IC 50 of 0.5 µM. Based on the close resemblance of ludartin (3) to arglabin (5) (position isomers), we also synthesized the amino analogs of ludartin [8], wherein compound 9 displayed a selective and potent biological effect, and, finally, we also developed a route for the hemisynthesis of arglabin from ludartin [9]. Arglabin, along with its dimethylamine analog (11R)-13-(dimethylamine)-11,13-dihydroarglabin (6), is an approved anticancer agent in several countries for the treatment of lung, liver, breast, and ovarian cancers [10, 11].…”

mentioning

confidence: 99%

“…A library of analogs was prepared whose formation could easily be confirmed by the disappearance of two diagnostic proton resonances at δ 5.38 ppm (d, J = 3.5 Hz) and δ 6.21 ppm (d, J = 3.5 Hz) of the α-methylene protons (13 H 2 ) of ludartin (3) as well as its epoxy analog (11). Since ludartin bears five contiguous chiral centers (C-3,4,5,6,7), Michael addition creates one more chiral center at the C-11 position, with R configuration [8]. Further epoxidation created two more chiral centers in the molecule, making the total number of chiral centers in any 1,10-epoxy-11R,13-aminoludartin analog equal to eight.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Lone

Bhat

Malik

et al. 2016

PMIO

View full text Add to dashboard Cite

Abstract! Diverse 11R,13-dihydroamino and 1,10β-epoxy-11R,13-dihydroamino analogs of ludartin were synthesized using a highly diastereoselective Michael addition and epoxidation reaction. The semisynthetic analogs were characterized using rigorous spectral data analysis. All the compounds were subjected to sulphorhodamine B cytotoxicity screening against a panel of three breast cancer cells, viz., T47D, MCF-7, and MDA-MB 231. Among the synthesized analogs, compounds 11, 19, and 20 proved to be active against the breast cancer cell lines. Compound 11 represents an epoxy analog of arglabin (5), which is a noteworthy and clinically significant antitumor agent and exhibited an IC 50 s of 0.75 µM and 1.20 µM against MCF-7 and MDA MB-231 cell lines, respectively. Compounds 19 and 20 displayed selectivity among the three breast cancer cell lines and were active against MCF-7 cell lines only displaying IC 50 s of 1.00 and 1.21 µM, respectively. This study provides initial structure-activity relationship data on ludartin and its analogs against breast cancer cell lines based on the previous literature reports of ludartin as an aromatase inhibitor.Key words ludartin · amino analogs · epoxy amino analogs · breast cancer · cytotoxicity Supporting information available online at http://www.thieme-connect.de/products Leaving apart the cancers of skin, breast cancer is the most frequently occurring cancer in women [1]. It ranks second as a cause of tumor-related death only after lung cancer. Presently, it is envisaged that one in eight American women will develop breast cancer sometime during her life. Two-thirds of breast cancer tumors are hormone dependent, requiring estrogen to flourish [2]. An effective approach to treat such hormone-dependent cancer involves interfering with hormone production. Aromatase, or estrogen synthase, has always been considered the most promising target for the endocrine treatment of breast cancer [3]. Among all inhibitors, nonsteroidal inhibitors have proved to be the best therapeutic agents, as they reversibly inhibit the enzyme [2,4]. Aromatase inhibitors (AIs) are further divided into categories based on the order in which they were discovered or synthesized: first-, second-, and third-generation AIs. Currently, the third generation aromatase inhibitors are triazole-derived AIs and are approved as front-line therapy for early and advanced cases of breast cancer in postmenopausal women [1,5,6]. Brueggemeier and Cruz [1] framed a list of 65 molecules with potent aromatase inhibitory activity, among which the four sesquiterpene lactones, designated 1, 2, 3, and 4 (l " Fig. 1), display strong aromatase inhibition. The research group opined that the triazole-based compounds display a potent inhibitory effect. Taking a cue from this literature, we previously synthesized the 1, 2, 3 triazole-based analogs [7] of this molecule to develop more potent and less toxic compounds, and screened them against breast cancer cells. Among all of the synthesized compounds, only one compound, namely, (11R)-13-[1-(...

show abstract

mentioning

confidence: 70%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Lone

Bhat

Malik

et al. 2016

PMIO

View full text Add to dashboard Cite

show abstract

“…It has been found that changing from one AI-class to another, regardless of the sequence, can result in 0-26% ORR and that 50-62% of these patients achieve stable disease (Thürlimann et al 1997, Zilembo et al 2004, Bertelli et al 2005, Chia et al 2008, Miller et al 2008. The exact mechanism of nontotal cross-resistance however is not yet known.…”

Section: Perspectivesmentioning

confidence: 99%

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Asten¹,

Neven²,

Lintermans³

et al. 2014

Endocrine-Related Cancer

View full text Add to dashboard Cite

Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total crossresistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

show abstract

“…The development progressed from non-selective to selective non-steroid inhibitors of aromatase, such as letrosol and anastrosol, which block estrogen production (29). The importance of aromatase quantity in tumours was evaluated by Miller et al (31). They observed that most tumours obtain estrogen thanks to both local and peripheral aromatase.…”

Section: Antiestrogens and Phytoestrogensmentioning

confidence: 99%

Naturally Occurring Substances and Their Role in Chemo-protective Effects

Rabajdová¹,

Birková²,

Urban³

et al. 2013

Cent Eur J Public Health

View full text Add to dashboard Cite

SUMMARYCancer chemoprevention is defined as the use of natural, synthetic or biological chemical agents to reverse, suppress or prevent carcinogenic progression of invasive cancer. Carcinogenesis is a complex multi-step process; therefore, it is necessary to attack cell proliferation, stimulate apoptosis and inhibit angiogenesis. There have been more than 60 randomised trials using chemopreventive potential agents.The success of several recent clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational and appealing strategy. In this review, we describe the conceptual basis for the chemoprevention of cancer, proven concepts of efficiency and current trends in the use of chemopreventive agents according to place and mechanism of action. We classify chemopreventive substances into seven groups based on their chemical structure and their effects, namely, deltanoids (paracalcitriol), retinoids (13-cis retinoic acid), non-steroidal anti-rheumatics (Deguelin), antiestrogens (genistein), polyphenols (curcumin), sulphur containing compounds (sulforaphane) and terpenes (lycopene). Chemoprevention is one of several promising strategies for reducing the incidence of malignant tumours or helping to prolong the time before recurrence.

show abstract

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

Cited by 99 publications

References 59 publications

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Naturally Occurring Substances and Their Role in Chemo-protective Effects

Contact Info

Product

Resources

About