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Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer.

Collery P, Mohsen A, Kermagoret A, Corre S, Bastian G, Tomas A, Wei M, Santoni F, Guerra N, Desmaële D, d'Angelo J - Invest New Drugs (2015)

Bottom Line: We now disclose an improved synthesis of this complex.Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d.We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

View Article: PubMed Central - PubMed

Affiliation: Société de Coordination de Recherches Thérapeutiques, Algajola, France, philippe.collery@gmail.com.

ABSTRACT
Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

No MeSH data available.


Related in: MedlinePlus

Synthesis of 1 with optimized approach to key-intermediate 4. Reagents and conditions, i: BrCH2CO2Me, NaBH4, EtOH, 16 h, 20 °C (82 %); ii: LiOH.H2O, THF, MeOH, 16 h, 20 °C (85 %); iii: ReCl(CO)5, THF, reflux, 16 h (72 %); iv: 2.0 equiv. NaHCO3, MeOH,H2O, 0 °C (90 %); v: ReCl(CO)5, THF, reflux, 16 h (68 %)
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Sch1: Synthesis of 1 with optimized approach to key-intermediate 4. Reagents and conditions, i: BrCH2CO2Me, NaBH4, EtOH, 16 h, 20 °C (82 %); ii: LiOH.H2O, THF, MeOH, 16 h, 20 °C (85 %); iii: ReCl(CO)5, THF, reflux, 16 h (72 %); iv: 2.0 equiv. NaHCO3, MeOH,H2O, 0 °C (90 %); v: ReCl(CO)5, THF, reflux, 16 h (68 %)

Mentions: Although the published synthesis of complex 1 has proved rather efficient, the elaboration of a key intermediate (compound 4 in scheme 1) was somewhat problematic, since suffering from a vexing lack of reproducibility. For that reason, we have recently developed an alternative approach to key-compound 4, which has proved perfectly reproducible. This new protocol involved the alkylation of the disodium salt of propane-diselenocyanate 2 with bromoacetic acid methyl ester, giving diester 3, which was next saponified with lithium hydroxide into diacid 4. Complexation of ReCl(CO)3 by diselenoether 4, followed by sodium bicarbonate treatment provided complex 1, as previously reported [8]. Likewise, to study the possible interactions of the complex with DNA bases without competitive attack of the carboxylate appendages on the Re atom, the corresponding dimethyl ester complex 5 was prepared by condensation of diselenoester 3 with ReCl(CO)3 in 68 % yield.Scheme 1


Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer.

Collery P, Mohsen A, Kermagoret A, Corre S, Bastian G, Tomas A, Wei M, Santoni F, Guerra N, Desmaële D, d'Angelo J - Invest New Drugs (2015)

Synthesis of 1 with optimized approach to key-intermediate 4. Reagents and conditions, i: BrCH2CO2Me, NaBH4, EtOH, 16 h, 20 °C (82 %); ii: LiOH.H2O, THF, MeOH, 16 h, 20 °C (85 %); iii: ReCl(CO)5, THF, reflux, 16 h (72 %); iv: 2.0 equiv. NaHCO3, MeOH,H2O, 0 °C (90 %); v: ReCl(CO)5, THF, reflux, 16 h (68 %)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4491361&req=5

Sch1: Synthesis of 1 with optimized approach to key-intermediate 4. Reagents and conditions, i: BrCH2CO2Me, NaBH4, EtOH, 16 h, 20 °C (82 %); ii: LiOH.H2O, THF, MeOH, 16 h, 20 °C (85 %); iii: ReCl(CO)5, THF, reflux, 16 h (72 %); iv: 2.0 equiv. NaHCO3, MeOH,H2O, 0 °C (90 %); v: ReCl(CO)5, THF, reflux, 16 h (68 %)
Mentions: Although the published synthesis of complex 1 has proved rather efficient, the elaboration of a key intermediate (compound 4 in scheme 1) was somewhat problematic, since suffering from a vexing lack of reproducibility. For that reason, we have recently developed an alternative approach to key-compound 4, which has proved perfectly reproducible. This new protocol involved the alkylation of the disodium salt of propane-diselenocyanate 2 with bromoacetic acid methyl ester, giving diester 3, which was next saponified with lithium hydroxide into diacid 4. Complexation of ReCl(CO)3 by diselenoether 4, followed by sodium bicarbonate treatment provided complex 1, as previously reported [8]. Likewise, to study the possible interactions of the complex with DNA bases without competitive attack of the carboxylate appendages on the Re atom, the corresponding dimethyl ester complex 5 was prepared by condensation of diselenoester 3 with ReCl(CO)3 in 68 % yield.Scheme 1

Bottom Line: We now disclose an improved synthesis of this complex.Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d.We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

View Article: PubMed Central - PubMed

Affiliation: Société de Coordination de Recherches Thérapeutiques, Algajola, France, philippe.collery@gmail.com.

ABSTRACT
Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

No MeSH data available.


Related in: MedlinePlus