Patrick Herson

Ferrocenyl Quinone Methides as Strong Antiproliferative Agents: Formation by Metabolic and Chemical Oxidation of Ferrocenyl Phenols†

The modification of the biological effects of some biologically active molecules by ferrocene is an active field of study. The addition of a ferrocenyl moiety to selected polyaromatic phenols, amines, and amides can potentiate their antiproliferative effects against breast and prostate cancer cells. For example, hydroxytamoxifen, the active metabolite of the breast cancer drug tamoxifen, shows limited toxicity against hormone-refractory breast cancer cells (IC50 for MDA-MB231: 29 mm). However, when a phenyl group is replaced by a ferrocene moiety, the resulting “hydroxyferrocifen” displays a dramatic improvement in toxicity (IC50 = 0.5 mm). [6] In 2006, we proposed in this journal a novel mechanism of activation of ferrocene phenols: their ferrocene-mediated oxidation to quinone methide (QM) metabolites. This work was subsequently featured as part of a Highlight article. Quinone metabolites are potentially cytotoxic species, and, when ferrocene is present, QM formation takes place at comparatively mild (i.e. biologically relevant) oxidation potentials. Furthermore, the observation that some cancer cells are under heightened oxidative stress suggests that this class of redox-activated compounds may show an interesting selectivity profile. The formation of ferrocenyl QMs has been supported only by electrochemical experiments until now. We herein show that QMs do form upon metabolism of 1–4 by rat liver

Anderson-Type Heteropolymolybdates Containing Tris(alkoxo) Ligands: Synthesis and Structural Characterization

Anderson-type molybdopolyanions containing tris(alkoxo) ligands [MMo6O18{(OCH2)3CR}2]3− (M = MnIII, FeIII) and [H2MMo6O18{(OCH2)3CR}2]2− (M = NiII, ZnII), (R = CH3, NO2, CH2OH), were prepared by treatment of [N(C4H9)4]4[α-Mo8O26] with tris(hydroxymethyl)methane derivatives in the presence of manganese(III) acetylacetonate, iron(III) acetylacetonate, nickel(II) acetate, or zinc(II) acetate. The complexes were structurally characterized in solution, and also by single-crystal X-ray diffraction in the cases of [N(C4H9)4]3[MnMo6O18{(OCH2)3CNO2}2], [N(C4H9)4]2[H2NiMo6O18{(OCH2)3CCH2OH}2], and [N(C4H9)4]2[H2ZnMo6O18{(OCH2)3CCH3}2]. Two tris(alkoxo) ligands replace the six hydroxo groups usually found in Anderson polyanions of formula [H6MMo6O24]n−. The complex structures may be divided into two groups: In the first one the tris(alkoxo) ligands are bound entirely to the central heteroatom, while in the second one they cap a tetrahedral cavity. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Interplay of Cubic Building Blocks in (η6-arene)Ruthenium-Containing Tungsten and Molybdenum Oxides

A series of molybdenum and tungsten organometallic oxides containing [Ru(arene)]2+ units (arene =p-cymene, C6Me6) was obtained by condensation of [[Ru(arene)Cl2]2] with oxomolybdates and oxotungstates in aqueous or nonaqueous solvents. The crystal structures of [[Ru(eta6-C6Me6]]4W4O16], [[Ru(eta6-p-MeC6H4iPr]]4W2O10], [[[Ru-(eta6-p-MeC6H4iPr)]2(mu-OH)3]2][[Ru(eta6-p-MeC6H4iPr)]2W8O28(OH)2[Ru(eta6-p-MeC6H4iPr)(H2O)]2], and [[Ru(eta6-C6Me6)]2M5O18[Ru(eta6-C6Me6)(H2O)]] (M = Mo, W) have been determined. While the windmill-type clusters [[Ru(eta6-arene)]4(MO3)4(mu3-O)4] (M = Mo, W; arene =p-MeC6H4iPr, C6Me6), the face-sharing double cubane-type cluster [[Ru(eta6-p-MeC6H4iPr)]4(WO2)2(mu3-O)4(mu4-O)2], and the dimeric cluster [[Ru(eta6-p-MeC6H4iPr)(WO3)3(mu3-O)3(mu3-OH)Ru(eta6-pMeC6H4iPr)(H2O)]2(mu-WO2)2]2- are based on cubane-like units, [(Ru(eta6-C6Me6)]2M5O18[Ru(eta6-C6Me6)(H2O)]] (M = Mo, W) are more properly described as lacunary Lindqvist-type polyoxoanions supporting three ruthenium centers. Precubane clusters [[Ru(eta6-arene)](MO3)2(mu-O)3(mu3-O)]6- are possible intermediates in the formation of these clusters. The cluster structures are retained in solution, except for [[Ru(eta6-p-MeC6H4iPr)]4Mo4O16], which isomerizes to the triple-cubane form.

[CrIII(L)(CN)4]−: a new building block in designing cyanide-bridged 4,2-ribbon-like chains {[CrIII(L)(CN)4]2Mn(H2O)2}·nH2O [L = 2-aminomethylpyridine (n = 6) and 1,10-phenanthroline (n = 4)]

The preparation, X-ray crystallography and magnetic study of compounds PPh4[Cr(ampy)(CN)4]·H2O (1), PPh4[Cr(phen)(CN)4]·H2O·CH3OH (2), {[Cr(ampy)(CN)4]2Mn(H2O)2}·6H2O (3) and {[Cr(phen)(CN)4]2Mn(H2O)2}·4H2O (4), with PPh4+ = tetraphenylphosphonium cation, ampy = 2-aminomethylpyridine and phen = 1,10-phenanthroline, are reported here. 1 and 2 are mononuclear complexes whereas 3 and 4 are 4,2-ribbon-like bimetallic chains. The magnetic properties of 1–4 were investigated in the temperature range 1.9–300 K. A quasi Curie law behaviour for a magnetically isolated spin quartet is observed for 1 and 2. Compounds 3 and 4 are ferrimagnetic CrIII2MnII chains, which exhibit a metamagnetic behaviour, the values of the critical field being Hc = 1 T (3) and 5000 G (4), which is due to the occurrence of weak interchain antiferromagnetic interactions. Below ca. 4.0 K, compound 4 shows a spin-canted structure with a narrow hysteresis loop, the value of the coercive field being 50 G.

Further studies of the norditerpene (+)-harringtonolide isolated from Cephalotaxus harringtonia var. drupacea: absolute configuration, cytotoxic and antifungal activities.

Harringtonolide (= hainanolide) is a complex polycyclic fused norditerpene isolated from CEPHALOTAXUS HARRINGTONIA var. DRUPACEA. In spite of its appealing biological properties - we measured an IC (50) of 43 nM on KB cells and a significant antifungal activity - its absolute configuration has not yet been firmly established. This was done herein using X-ray anomalous scattering after bromination of the tropone ring, unambiguously giving the stereochemistry 5 R,6 R,7 S,13 S,14 S,15 R,16 R. Detailed IN VITRO biological measurements are provided.

Verdazyl-based extended structures: synthesis, structures and magnetic properties of silver(I) one dimensional compounds

The reactions of silver(I) perchlorate with 3-(4,6-dimethyl-2-pyrimidyl)-1,5-dimethyl-1,2,4,5-tetrazane 6-oxide and its oxidized form, the radical 3-(4,6-dimethyl-2-pyrimidyl)-1,5-dimethyl-6-oxoverdazyl, afford one-dimensional compounds 1 and 2. Single crystal X-ray diffraction shows that both compounds are built from cationic chains of silver(I) ions bridged by bidentate ligands. The one-dimensional objects are isolated from one another by perchlorate ions and solvent molecules. The oxidation state of the ligands is preserved during the reaction, even under aerobic conditions. The verdazyl derivative presents an intrachain antiferromagnetic exchange interaction J = −7.5 cm−1 (H = −JΣSi·Si+1) between two radicals through the diamagnetic silver(I) ion.

Asymmetric Synthesis of the Oxygenated Polycyclic System of (+)-Harringtonolide

A straightforward asymmetric synthesis of the cage oxygenated structure of (+)-harringtonolide has been accomplished for the first time. The key steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring D, (ii) functionalization of the cycloadduct, (iii) ring-closing metathesis providing the five-membered ring C, and finally (iv) a challenging one-step cascade cyclization of an epoxy-alcohol toward the target structure, whose mechanism was investigated.

Overall “Pseudocationic” Trifluoromethylation of Dihydropyridines with Triflic Anhydride

The starting materials for all those transformations were differently substituted pyridines, which underwent stepwise nucleophilic addition reactions with ketene acetals 1 upon activation by methyl chloroformate. The ring-closure reaction, leading from 2 to 3, is stereospecific: only the transdiaxial-oriented functionalized lactones are formed. These transformations are part of a special class of reactions of dihydropyridines: nonbiomimetic oxidations, which do not lead, as one would expect, to pyridinium salts. Indeed, the electrophiles preferentially react with one of the double bonds of the ene-carbamates 2 than with the proton at C4. The activation of the pyridinium nucleus towards carbon nucleophiles is not limited to alkyl chloroformates or acid chlorides, since several research groups have also used triflic anhydride for that purpose; in addition to the higher stability of the intermediate pyridinium salts and the general higher yields of the addition products, the absence of rotamers at room temperature is also beneficial. For the purpose of comparing the two activation procedures, with methyl chloroformate or triflic anhydride, we synthesized a series of dihydropyridines subsituted by a triflyl group on the nitrogen atom. This led us to the discovery of a new, unexpected transformation of these dihydropyridines. Thus, the reaction of pyridine with ketene acetals 1a,b (1 equiv) and then with triflic anhydride (1 equiv) at 30 8C led, as expected, after warming the mixture to room temperature and stirring for 17 h, to the same type of acid-substituted dihydropyridines 7a,b in high yield (97%, Scheme 2). Although the reaction of these dihydropyridines with either silica gel or an anhydrous solution of HCl in diethyl ether did not lead to the expected lactones 8a,b, they did react with I2 and CuBr2 to give, as for 2, the corresponding halolactones 9 (Scheme 3).

(Ferrocenylmethyl)trialkyl ammoniums as template cations in optically active two-dimensional oxalate bridged [Cr–Mn] and [Cr–Ni] molecule-based magnets: synthesis and magnetic properties

Abstract A series of (ferrocenylmethyl)trialkyl ammoniums: FcCH2NR3+ with R=CH3 (1), C2H5 (2), n-C3H7 (3), n-C4H9 (4) (X-ray structure provided), n-C5H11 (5) and the planar chiral 1,2-disubstituted Fc(CH3)CH2NBu3+ (6) have been tentatively used as template cation in order to synthesise bidimensional (2D) oxalate bridged molecule-based magnets of general formula {[CrIIIMII(ox)3][FcCH2NR3]}n and{[CrIIIMII(ox)3][Fc(CH3)CH2NBu3]}n (M=Mn2+, Ni2+, ox=C2O42−). These polymeric compounds were obtained only for reactions performed with 2, 3, 4 and 6. Starting from resolved Cr(ox)32−, the networks were prepared in their two enantiomeric forms in the case of {[CrIIINiII(ox)3][FcCH2NBu3]}n ([CrΔ–NiΛ]-4 and [CrΛ–NiΔ]-4) or {[CrIIIMnII(ox)3][FcCH2NBu3]}n ([CrΔ–MnΛ]-4 and [CrΛ–MnΔ]-4)) and characterised by circular dichroism measurements. All these compounds are ferromagnets with a Curie temperature close to 6 K when M=Mn and to 17 K for Ni. While the manganese [Cr–Mn] containing compounds are soft magnets, the [Cr–Ni] networks show coercive force up to 2200 Oe far above those previously reported for these networks.

A new organometallic heteropolytungstate related to [Sb2W22O74(OH)2]12−: synthesis and structural characterisation of the bis-{Ru(p-cymene)}2+-containing anion [Sb2W20O70{Ru(p-cymene)}2]10−

The easy synthesis of [Sb2W20O70{Ru(p-cymene)}2](10-) by the reaction between the organometallic precursor [Ru(p-cymene)Cl2]2 and [Sb2W20O70]14-, formed in situ, confirms the importance of the organometallic route to well defined ruthenium(+II)-substituted heteropolytungstates.