Synthesis, antiproliferative activity and estrogen receptor α affinity of novel estradiol-linked platinum(II) complex analogs to carboplatin and oxaliplatin. Potential vector complexes to target estrogen-dependent tissues

Saha, Pijus; Descôteaux, Caroline; Brasseur, Kevin; Fortin, Sébastien; Leblanc, Valérie; Parent, Stefan; Asselin, Éric; Bérubé, Gervais

doi:10.1016/j.ejmech.2011.12.017

Cited by 46 publications

(33 citation statements)

References 25 publications

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“…This steroid-targeting strategy was also applied to derivatives of carboplatin and oxaliplatin. 124 Recently, this strategy was extended with the design and synthesis of a 17β-acetyl-testosterone conjugate linked to the platinum center through the 7α position. 125 In the same way that estrogen units can target cancer cells expressing the ER, testosterone can target platinum to cancer cells expressing the androgen receptor (AR).…”

Section: Platinum(ii) Compounds With a Mechanism Of Action Similarmentioning

confidence: 99%

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

2016

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The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive.

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Section: Platinum(ii) Compounds With a Mechanism Of Action Similarmentioning

confidence: 99%

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

2016

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“…Analogues of cisplatin, carboplatin and oxaliplatin have been prepared with estrogens-like compounds in order to increase selectivity towards hormone-dependent breast, ovarian and uterine tumours (Descôteaux et al, 2003(Descôteaux et al, , 2008Saha et al, 2012). The estrogens-derived cisplatin and carboplatin ligands possess a high affinity for the oestrogen Fig.…”

Section: Cisplatin and Transplatinmentioning

confidence: 99%

Coordination compounds in cancer: Past, present and perspectives

Trudu¹,

Amato

Vaňhara³

et al. 2015

J Appl Biomed

136

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“…Estradiol was substituted at position 16 rather than at position 3 or 17 because the hydroxyl groups at these positions (3 and 17) are important for receptor binding affinity [18]. In addition, position 16 has already shown promising results when estrogen was conjugated to platinum complexes [22][23][24][25][26][35][36][37][38][39]. Moreover, the length of the alkyl linking arm between estrogen substituted at position 16 and the platinum complexes is an important parameter for the biological activity and the affinity of the conjugate to the receptor.…”

Section: Design Of E-doxmentioning

confidence: 99%

“…Moreover, the length of the alkyl linking arm between estrogen substituted at position 16 and the platinum complexes is an important parameter for the biological activity and the affinity of the conjugate to the receptor. The biological activity and the affinity for the receptor are both optimal when the alkyl spacer has 6 to 10 carbon atoms in length [22,23,35,38]. We therefore decided to investigate the same parameter on our novel E-DOXs by varying the length of the alkylamide linking arm between estrogen and DOX from 3 to 9 carbon atoms (E-DOX 8a-d).…”

Section: Design Of E-doxmentioning

confidence: 99%

“…Interestingly, these results indicate that alkylamide linking arm between estrogen substituted at position 16 and DOX is also an important parameter for the antiproliferative activity and the affinity for the ER as observed when using platinum complexes. However, the antiproliferative activity of platinum complexes increases with the lengthening of the alkyl spacer length and is optimal when the alkyl spacer bears 6 to 10 carbon atoms [22,23,35,38] contrary to E-DOX, which require a shorter alkylamide spacer arm (< 5 carbon atoms) for maintain both significant antiproliferative activity and affinity with ER. These results are underlying the fact that each element of the anticancer drug conjugates to estrogen (e.g., nature of the anticancer drugs, nature and the alkyl spacer chain length) plays an important role in the antiproliferative activity and its ability to target ER + breast cancers.…”

Section: Chemistrymentioning

confidence: 99%

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Design, synthesis, cytocidal activity and estrogen receptor α affinity of doxorubicin conjugates at 16α-position of estrogen for site-specific treatment of estrogen receptor positive breast cancer

Saha¹,

Fortin²,

Leblanc³

et al. 2012

Steroids

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Doxorubicin (DOX) is an important medicine for the treatment of breast cancer, which is the most frequently diagnosed and the most lethal cancer in women worldwide. However, the clinical use of DOX is impeded by serious toxic effects such as cardiomyopathy and congestive heart failure. Covalently linking DOX to estrogen to selectively deliver the drug to estrogen receptor-positive (ER(+)) cancer tissues is one of the strategies under investigation for improving the efficacy and decreasing the cardiac toxicity of DOX. However, conjugation of drug performed until now was at 3- or 17-position of estrogen, which is not ideal since the hydroxyl groups at this position are important for receptor binding affinity. In this study, we designed, prepared and evaluated in vitro the first estrogen-doxorubicin conjugates at 16α-position of estradiol termed E-DOXs (8a-d). DOX was conjugated using a 3-9 carbon atoms alkylamide linking arm. E-DOXs were prepared from estrone using a seven-step procedure to afford the desired conjugates in low to moderate yields. The antiproliferative activities of the E-DOX 8a conjugate through a 3-carbon spacer chain on ER(+) MCF7 and HT-29 are in the micromolar range while inactive on M21 and the ER(-) MDA-MB-231 cells (>50 μM). Compound 8a exhibits a selectivity ratio (ER(+)/ER(-) cell lines) of >3.5. Compounds 8b-8d bearing alkylamide linking arms ranging from 5 to 9 carbon atoms were inactive at the concentrations tested (>50 μM). Interestingly, compounds 8a-8c exhibited affinity for the estrogen receptor α (ERα) in the nanomolar range (72-100 nM) whereas compound 8d exhibited no affinity at concentrations up to 215 nM. These results indicate that a short alkylamide spacer is required to maintain both antiproliferative activity toward ER(+) MCF7 and affinity for the ERα of the E-DOX conjugates. Compound 8a is potentially a promising conjugate to target ER(+) breast cancer and might be useful also for the design of more potent E-DOX conjugates.

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Synthesis, antiproliferative activity and estrogen receptor α affinity of novel estradiol-linked platinum(II) complex analogs to carboplatin and oxaliplatin. Potential vector complexes to target estrogen-dependent tissues

Cited by 46 publications

References 25 publications

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Coordination compounds in cancer: Past, present and perspectives

Design, synthesis, cytocidal activity and estrogen receptor α affinity of doxorubicin conjugates at 16α-position of estrogen for site-specific treatment of estrogen receptor positive breast cancer

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