Synthesis of ferrocenyl oxindole compounds with potential anticancer activity

Abstract

Compostos oxindol-ferrocenos com potencial atividade anticâncer foram preparados a partir de reações de oxindóis substituídos e carboxaldeído-ferroceno na presença de KOH como catalisador. Os produtos foram caracterizados por dados espectroscópicos incluindo RMN de 1 H e 13 C, infravermelho e espectrometria de massas. As configurações E e Z foram estabelecidas por experimentos de nOe ou NOESY.A series of ferrocenyl oxindoles with potential anticancer activity were prepared from the reactions of substituted oxindoles and ferrocenylcarboxyaldehyde in the presence of KOH as catalyst. The products were characterized by spectral data including 1 H and 13 C NMR, IR and mass spectrometry. The E and Z configurations were established by nOe or NOESY experiments. Keywords: ferrocenyl oxindoles, oxindoles, ferrocenecarboxyaldehyde IntroductionThe ferrocenyl (Fc) group has been incorporated to the structure of a number of biologically active molecules resulting in increased anticancer 1,2 and antimalarial [3][4][5] activity, amongst others. Addition, alkylation, acylation, condensation-dehydration, coupling and nucleophilic substitution reactions have been employed to link this group to a variety of compounds. [2][3][4]6,7 The mechanisms of the cytotoxicity of ferrocene derivatives have been investigated.8 Osella et al. 9 proposed that the cytotoxic activity of ferrocenium salts is due to their ability to generate oxygen active species that induce oxidative DNA damage. Kondapi et al. 10,11 have shown that ferrocene derivatives inhibit topoisomerase II, a major molecular target for a number of DNA-binding anticancer drugs.Indolin-2-ones have been shown to exhibit antitumor activity by inhibiting receptor tyrosine kinases VEGF-R, PDGF-R or CDK.12 The indolin-2-one 1 (sunitinib) has been approved by the U.S. We describe herein the condensation reactions of several oxindole derivatives with FcC(O)H in the presence of KOH in EtOH from which good to excellent yields of the products with E and Z configurations were obtained (Scheme 1). 16The products were characterized by mass spectrometry and infrared, 1 H and 13 C NMR spectroscopies, including nOe and NOESY experiments for the determination of the double-bond geometry. 1245 Vol. 19, No. 7, 2008 Preliminary studies of the reaction of oxindole with FcC(O)H (Table 1) were carried out to assess the catalytic potential of various bases. Except for Et 3 N, all the bases employed led to good conversions. However, formation of products with both E and Z configurations depend on the base employed. The use of KOH in EtOH gave the best yield and selectivity for the E-isomer 2a (entry 1). In the presence of piperidine (entry 3) we were able to isolate the E-isomer 2a in 67% yield together with a 30% isolated yield for the corresponding Z-isomer 2b. The geometries of isomers 2a and 2b were determined by nOe experiments and NOESY interactions. The NOESY experiment for 2a shows a correlation between H4 and H2' of the cyclopentadienyl ring, thus revealing an (E)-configuration for this isom...

The Knoevenagel product of indolin-2-one and ferrocene-1,1′-dicarbaldehyde

“…Of interest, three of a set of seven substituted 3-methylideneindolin-2-ones (Spencer et al, 2010) and one of the two isomeric ferrocenyl oxindoles (Spencer et al, 2009) previously reported by us also have Z 0 > 1. The geometry of both crystallographically independent ferrocene species in (IV) are comparable with the ferrocenyl oxindoles and substituted oxindoles previously reported by us and others (Silva et al, 2008;Spencer et al, 2009Spencer et al, , 2010 and with fragments found in a search of the Cambridge Structural Database (CSD, Version 5.32; Allen, 2002). All four oxindole units in (IV) exist as the (E)-isomers, with the average of the four bond angles C11/C111-C12/C112-C13/C113 and C20/C120-C21/C121-C22/C122 being 118.8 (5) .…”

“…We and others have recently published the synthesis of the isomeric ferrocenyl oxindoles, (E)-and (Z)-3-(ferrocenylmethylidene)indolin-2-one, denoted (E)and (Z)-(III), which are readily separated and have excellent anticancer properties (see scheme). We have shown that (E)and (Z)-(III) display intermolecular NHÁ Á ÁO C hydrogen bonding in the solid state (Silva et al, 2008;Spencer et al, 2009).…”

Organometallic Complexes: New Tools for Chemotherapy

“…As a result, ferrocene was incorporated into a large number of molecules such as water soluble polymers [61][62][63][64], DNA intercalator [65], phosphino compounds [66][67][68][69], and other biomolecules [70][71][72][73]. Diferrocenyl compounds [74] and a variety of other small ferrocenyl molecules [75][76][77][78][79] have also been investigated for anticancer activity.…”

Synthesis and biological activity of novel statine derivatives containing ferrocenyl moiety

“…Among metallocenes there are compounds with antiproliferative effect, antibiotics, and inhibitors of enzymes. [6][7][8][9] Conjugates of ferrocene with well-known drugs were reported. [10][11] Ferrocene-containing compounds often possess unexpected biological activity.…”