When carefully selected substituents are added to the basic skeleton of hormonal steroids, there can be considerable changes in the properties of the new compound. The 11β position is particularly amenable to such changes. Mifepristone (RU 486) (Scheme 1) owes its antiprogestin properties to the –C6H4-N(Me)2 group attached at position 11β [1], [2] and [3], while in the estrogen series, attachment of a long chain, either N-butylundecanamide or a polyfluoroalkylthio group, at 11β turns the new compound into antiestrogens such as RU 39411 [4] or RU 58668 [5]. Similarly, the 11β-CH2Cl attached to the estradiol framework (ORG 4333) causes a spectacular increase in the affinity of the modified compound for the estrogen receptor [6] and [7]. Although many organometallic moieties, i.e. those with a metal–carbon bond, have been attached at various positions on the estradiol skeleton [8], [9], [10], [11], [12], [13] and [14], the attachment of an organometallic fragment at the strategic 11β position is very rare [3]. We present here the synthesis, several noteworthy biochemical properties and study of agonist or antagonist effect of 11β-[(ethynyl)Co2(CO)6]estradiol (1). Recently, antitumoral properties have been shown in vitro for some alkyne Co2(CO)6 organometallic complexes such as Co2(CO)6[2-propynyl acetyl salicylate] on melanoma and lung carcinoma cells but only at high concentrations (10–20 μM), while Co2(CO)8 itself shows no cytotoxic effect [15]. In vivo, alkylcobalt(III) chelate complexes, which are known to generate free radicals at low pH, have been shown to damage tumors such as ascite leukemia or Guerin carcinoma [16]. Assuming that recognition of the estrogen receptor is preserved in 1, this would provide a vehicle for introduction of a potential cytotoxic substance into estrogen-responsive tumors. The lack of specificity of most antitumoral agents, and the consequent damage to healthy tissue, remains a major problem in anti-cancer chemotherapy [17].
The First organometallic Derivative of 11b-Ethynylestradiol, a Potential High-Affinity Marker for the Estrogen Receptor
VINCENTI, Marco;
2000-01-01
Abstract
When carefully selected substituents are added to the basic skeleton of hormonal steroids, there can be considerable changes in the properties of the new compound. The 11β position is particularly amenable to such changes. Mifepristone (RU 486) (Scheme 1) owes its antiprogestin properties to the –C6H4-N(Me)2 group attached at position 11β [1], [2] and [3], while in the estrogen series, attachment of a long chain, either N-butylundecanamide or a polyfluoroalkylthio group, at 11β turns the new compound into antiestrogens such as RU 39411 [4] or RU 58668 [5]. Similarly, the 11β-CH2Cl attached to the estradiol framework (ORG 4333) causes a spectacular increase in the affinity of the modified compound for the estrogen receptor [6] and [7]. Although many organometallic moieties, i.e. those with a metal–carbon bond, have been attached at various positions on the estradiol skeleton [8], [9], [10], [11], [12], [13] and [14], the attachment of an organometallic fragment at the strategic 11β position is very rare [3]. We present here the synthesis, several noteworthy biochemical properties and study of agonist or antagonist effect of 11β-[(ethynyl)Co2(CO)6]estradiol (1). Recently, antitumoral properties have been shown in vitro for some alkyne Co2(CO)6 organometallic complexes such as Co2(CO)6[2-propynyl acetyl salicylate] on melanoma and lung carcinoma cells but only at high concentrations (10–20 μM), while Co2(CO)8 itself shows no cytotoxic effect [15]. In vivo, alkylcobalt(III) chelate complexes, which are known to generate free radicals at low pH, have been shown to damage tumors such as ascite leukemia or Guerin carcinoma [16]. Assuming that recognition of the estrogen receptor is preserved in 1, this would provide a vehicle for introduction of a potential cytotoxic substance into estrogen-responsive tumors. The lack of specificity of most antitumoral agents, and the consequent damage to healthy tissue, remains a major problem in anti-cancer chemotherapy [17].
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