Novel estradiol derivatives labeled with Ru,W, and Co complexes. Influence on hormone-receptor affinity of several organometallic groups at the 17 alpha position

In order to elucidate the extent to which recognition of the estrogen receptor is influenced by addition of an organometallic substituent at the 17 alpha position, modification of 17 beta-estradiol at this position was carried out by using the organometallic groups -C identical to C(eta 5-C5H4)RuCp, CH2-(eta 5-C5H4)RuCp, -C identical to C-(eta 5-C5H4)-W(CO)3(Me), -(C identical to CCHO)Co2(CO)6, and -(C identical to CCH2OH)Co2(CO)6. The relative binding affinity (RBA) values for estradiol receptor alpha showed that recognition was good (RBA between 20 and 13.5%) when the organometallic moiety was attached at the end of a rigid alkyne spacer. However, the affinity of the modified hormone for the receptor was severely reduced (RBA = 1%) for a substituent such as -CH2-(eta 5-C5H4)RuCP, in which the spacer is reduced to a single flexible sp3 carbon atom, allowing the organometallic moiety greater freedom of movement around the attachment point. The RBA values found were in agreement with results obtained from a molecular-modeling study in which 5, an organometallic hormone with a rigid spacer, or 7, a molecule with a flexible spacer, was inserted into the cavity of the recently characterized Ligand-Binding Domain of estrogen receptor alpha.     

Synthesis, biochemical properties and molecular modelling studies of organometallic specific estrogen receptor modulators (SERMs), the ferrocifens and hydroxyferrocifens: evidence for an antiproliferative effect of hydroxyferrocifens on both hormone-dependent and hormone-independent breast cancer cell lines

A series of ferrocene derivatives based upon the structure of the antiestrogenic drug tamoxifen or of its active metabolite hydroxytamoxifen has been prepared and named by analogy ferrocifens and hydroxyferrocifens. This series includes 1-[4-(O(CH(2))(n)NMe(2))phenyl]-1-phenyl-2-ferrocenyl-but-1-ene and 1-[4-(-O(CH(2))(n)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene, with n=2, 3, 5 and 8, and 1-[4-(-O(CH(2))(2)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenylethene. Most of these molecules have been synthesised by McMurry cross-coupling of the appropriate ketones, except for the ethene complexes, which were prepared by a four-step reaction sequence starting from the ferrocenylacetic acid. All these compounds were obtained as mixtures of Z and E isomers. The isomers were separated in the cases of the ferrocenyl derivatives of tamoxifen and hydroxytamoxifen (n=2). No isomerisation of the Z and E isomers occurred in DMSO after one day, while a 50:50 mixture of the isomers was obtained within one hour in chloroform. The X-ray structure of (E)-1-[4-(-O(CH(2))(2)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene has been determined. The relative binding affinity (RBA) values of the hydroxyferrocifens for the estrogen receptor alpha (ERalpha) was good to moderate, with values decreasing progressively with the length of the basic chain. The RBA values found for the estrogen receptor beta (ERbeta) are equal to or slightly less than those found for the alpha form. The lipophilicity of the hydroxyferrocifens are superior to the values found for estradiol and increase with lengthening of the chain. The antiproliferative effects of the four hydroxyferrocifens with n=2, 3, 5 and 8 were studied on four breast cancer cell lines (MCF7, MDA-MB231, RTx6 and TD5) possessing different levels of ERalpha. On MCF7 cells containing high levels of ERalpha, hydroxyferrocifens behave as antiestrogens. At a molarity of 1 microM the effect is close to that of hydroxytamoxifen (used for reference) when n=2 or 5, more marked when n=3, and weaker when n=8. Ferrocene alone has no effect. For the MDA-MB231 cells, classed as a hormone-independent breast cancer cell line, on the other hand, the hydroxyferrocifens show remarkable antiproliferative behaviour while the hydroxytamoxifen is completely inactive. Hydroxyferrocifens therefore show the unique property of being active both on hormone-dependent and on hormone-independent breast cancer cell lines. The molecular modelling study provides some clues for understanding of the antagonist effect of these molecules, while an additional cytotoxic effect due to the vectorised ferrocenyl unit is revealed in some occasions.     

Reactivity and reaction pathways of electrochemically generated 17-electron tricarbonyl steroid chromium cations

Electrochemical oxidation of α- and β-diastereomers of a range of steroid hormone receptor marker chromium tricarbonyl complexes, (steroid)Cr(CO)₃, have been examined at platinum electrodes in dichloromethane. Data confirm the general nature of previously published conclusions on the oxidation of (arene)Cr(CO)₃ complexes (arene = benzene or steroid). That is, with 0.1 M Bu₄NPF₆ as the electrolyte, and in the absence of nucleophiles, a reversible oneelectron process, (steroid)Cr(CO)₃ ? [(steroid)Cr(CO)₃]⁺ + e^?, is observed, followed by an irreversible one-electron process at considerably more positive potentials. The reversible half-wave potentials (approximately E°-values) calculated for the [(steroid)Cr(CO)₃]⁺/(steroid)Cr(CO)₃ redox couple are shown to be dependent on whether the α- or β-diastereomer is oxidized. Similarly the rate of nucleophilic attack on the 17-electron cation [(steroid)Cr(CO)₃]⁺ by nucleophiles such as ClO, PPh₃ and bis(diphenylphosphine)methane confirms a previous observation that the stereochemistry of this class of compound is important with respect to redox, kinetic and hormone receptor properties. The nature of the electrochemical data obtained on the (arene)Cr(CO)₃ complexes in the presence of nucleophiles suggests that reactions associated with the nucleophilic attack on the 17-electron cations are complex and that a range of reaction pathways occur simultaneously. Electrochemical studies on the oxidation of (benzene)Cr(CO)₂PPh₃ and (oestradiol)Cr(CO)₂PPh₃ confirm some aspects of the proposed mechanisms, although it is clear that a great deal still has to be learned concerning mechanistic aspects of nucleophilic attack on these 17-electron complexes.     

Modification of the Cp′ ring in the ferrocifen precursor and its influence on the recognition by the estrogen receptor

A synthetic pathway giving access to diphenyl ethylene organometallic derivatives possessing the ferrocifen precursor skeleton modified in the Cp′ ring is described. It relies on reaction of the (η⁵-propionylcyclopentadienyl) (η⁶-benzene)iron(II) salt 7 with substituted cyclopentadienyl anions or their heteroanalogs followed by the McMurry coupling reaction with 4,4′-dihydroxybenzophenone. Using this approach pentamethylcyclopentadienyl and 3,4-dimethylphospholyl analogs of ferrocifen precursor (10 and 11) have been synthesized. Even with the presence of the bulky and containing phosphorus η⁵-ligands these compounds are still recognized by the two subtypes of estrogen receptor(ERα and ERβ).     

New paradigms for synthetic pathways inspired by bioorganometallic chemistry

Two series of particular examples of reactions used in bioorganometallic chemistry are described. One based on a decomplexation-complexation reaction, indicates how, starting from a cymantrenyl derivative, a range of organometallic complexes bearing various metals can be prepared. The second one refers to the easy synthesis in water of the very versatile Alberto's reagent, which leads to new organometallic radiopharmaceuticals of Tc and Re.     

Ruled quartic surfaces,models and classification

New historical aspects of the classification, by Cayley and Cremona, of ruled quartic surfaces and the relation to string models and plaster models are presented. In a ‘modern’ treatment of the classification of ruled quartic surfaces the classical one is corrected and completed. The string models of Series XIII of some ruled quartic surfaces (manufactured by L. Brill and by M. Schilling) are based on a result of Rohn concerning curves in \mathbbP¹×\mathbbP¹{\mathbb{P}^1\times \mathbb{P}^1} of bi-degree (2, 2). This is given here a conceptional proof.     

Nonadiabatic transitions in chemical reactions: A quantum mechanical study

This work presents an exact quantum mechanical treatment of a reactive three-atom collinear model system incorporating nonadiabatic couplings. It was assumed that nonadiabatic transitions are induced by the vibrational motion only. The main findings are: (i) The reaction process can create conditions in which weak nonadiabatic couplings terms ( for which the Massey parameter was round 10) may cause large probabilities (～0.5) for transitions from one electronic surface to the other. In other words, the reaction process is able in certain cases to create a near resonance situation which makes the non-adiabatic transition almost independent of the magnitude of the coupling term. For this to happen the two surfaces need not be proximate, nor need they “almost” cross along a certain line (ii) In cases where the main nonadiabatic transitions take place outside the interaction region one may, at least qualitatively, decouple the reaction process from the nonadiabatic one. Thus, under the conditions specified one may first treat the reactive system on the ground state surface without including the excited interacting surface and then treat the nonadiabatic process independently.     

Metal complex SERMs (selective oestrogen receptor modulators). The influence of different metal units on breast cancer cell antiproliferative effects

The selective oestrogen receptor modulator tamoxifen is a leading agent in the adjuvant treatment of breast cancer. Several organometallic moieties have been vectorised with tamoxifen, in order to improve on the latter's antiproliferative properties by the addition of a potentially cytotoxic moiety, and have been evaluated versus both oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB231) breast cancer cells. For tamoxifen analogues with ((R,R)-trans-1,2-diaminocyclohexane)platinum(II), cyclopentadienyl rhenium tricarbonyl, and ruthenocene tethers, there was no enhancement of the antiproliferative effect on oestrogen receptor positive cells, nor any cytotoxic effect on oestrogen receptor negative cells, while those containing cyclopentadienyl titanium dichloride showed an oestrogenic effect. However, compounds where ferrocene replaces tamoxifen's phenyl ring were strongly cytotoxic against both cell lines. The synthesis and biological results of these compounds is reviewed and placed in the historic context of inorganic compounds in therapy.     

An Isogeny of K3 Surfaces

In a recent paper Ahlgren, Ono and Penniston described the L-seriesof K3 surfaces from a certain one-parameter family in termsof those of a particular family of elliptic curves. The Tateconjecture predicts the existence of a correspondence betweenthese K3 surfaces and certain Kummer surfaces related to theseelliptic curves. A geometric construction of this correspondenceis given here, using results of D. Morrison on Nikulin involutions.2000 Mathematics Subject Classification 14J27, 14G25, 14J28.