SciELO - Scientific Electronic Library Online

 
vol.19 issue7Triiodoisocyanuric acid: a new and convenient reagent for regioselective iodination of activated arenesNanochromics: old materials, new structures and architectures for high performance devices author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

  • English (pdf)
  • Article in xml format
  • How to cite this article
  • SciELO Analytics
  • Curriculum ScienTI
  • Automatic translation

Indicators

Related links

Share


Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.19 no.7 São Paulo  2008

http://dx.doi.org/10.1590/S0103-50532008000700003 

COMMUNICATION

 

Synthesis of ferrocenyl oxindole compounds with potential anticancer activity

 

 

Bárbara V. SilvaI, *; Núbia M. RibeiroI; Angelo C. PintoI; Maria D. VargasII; Luiz C. DiasIII

IInstituto de Química-CT, Bloco A, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21945-970 Rio de Janeiro-RJ, Brazil
IIInstituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Centro, 24020-150 Niterói-RJ, Brazil
IIIInstitute of Chemistry, University of Campinas, UNICAMP, P.O. Box 6154, 13084-971 Campinas-SP, Brazil

 

 


ABSTRACT

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 1H and 13C NMR, IR and mass spectrometry. The E and Z configurations were established by nOe or NOESY experiments.

Keywords: ferrocenyl oxindoles, oxindoles, ferrocenecarboxyaldehyde


RESUMO

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 1H e 13C, infravermelho e espectrometria de massas. As configurações E e Z foram estabelecidas por experimentos de nOe ou NOESY.


 

 

Introduction

The ferrocenyl (Fc) group has been incorporated to the structure of a number of biologically active molecules resulting in increased anticancer1,2 and antimalarial3-5 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.2-4,6,7 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-Rβ or CDK.12 The indolin-2-one 1 (sunitinib) has been approved by the U.S. Food and Drug Administration for the treatment of metastatic renal cell cancer and gastrointestinal stromal tumors13,14 (Figure 1). Raghunathan et al.15 reported recently the synthesis of the ferrocenyl oxindole 2a with (E)-configuration from the reaction of oxindole and ferrocenecarboxyaldehyde (FcC(O)H) in ethanol, in the presence of catalytic amounts of piperidine.

 

 

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).16 The products were characterized by mass spectrometry and infrared, 1H and 13C NMR spectroscopies, including nOe and NOESY experiments for the determination of the double-bond geometry.

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 Et3N, 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 isomer. In the case of 2b, we have observed a 2.15% intensity enhancement of the peak corresponding to H4 upon irradiation of H8, which confirms the (Z)-configuration (Figure 2).

 

 

The condensation reactions of a series of substituted oxindoles with FcC(O)H were then investigated in the presence of KOH in EtOH. Products and yields are summarized in Table 2.

 

 

The reactions of monosubstituted oxindoles 3, 4 and 10 (entries 1, 2 and 8, respectively) gave good conversions and the same product distribution as that of oxindole, with E-products being formed as the major isomers in yields above 90%. Product yields decreased with further ring substitution, and were also sensitive to the relative position of the substituents: whereas the reactions of 5,7-dichloro and 5,7-dibromo oxindoles (5 and 7, entries 3 and 5, respectively) gave both isomers albeit in lower yields than oxindole, those of the 4,7-dichloro and 4,6-dibromo oxindoles (6 and 8, entries 4 and 6, respectively) resulted only in the formation of the E-isomer in around 45% yields.

As shown in Table 3, in all cases, the olefinic hydrogen H8 of E-isomer (2a-10a) appear at higher frequency than for the Z-isomer (2b-10b), due to the diamagnetic anisotropy effect of the carbonyl oxygen (C2) on H8 of E-isomers 2a-10a. The same effect was observed for H3'and H5' of the Z-isomers 2b-10b. H8 chemical shifts for compounds 6a and 8a at d 8.40 and 8.34 pm, respectively, confirm the (E)-configuration.

 

 

Conclusion

In conclusion we have described a simple, fast and efficient synthetic route to ferrocenyl oxindoles, potential model compounds for chemical and pharmacological studies.

 

Acknowledgments

The authors thank the Brazilian agencies National Counsel for Technological and Scinentific Development (CNPq), State of Rio de Janeiro Research Foundation (FAPERJ), State of São Paulo Research Foundation (FAPESP) and Pronex-FAPERJ for financial support. We also thank Prof. Carol H. Collins (Institute of Chemistry, UNICAMP) for helpful suggestions about English grammar and style.

 

References

1. Top, S.; Tang, J.; Vessières, A.; Carrez, D.; Provot, C.; Jaouen, G.; Chem. Commun. 1996, 955.         [ Links ]

2. Hillard, E. A.; Pigeon, P.; Vessières, A.; Amatore, C.; Jaouen, G.; Dalton Trans. 2007, 5073.         [ Links ]

3. Domarle, O.; Blampain, G.; Agnaniet, H.; Nzadiyabi, T.; Lebibi, J.; Brocard, J.; Maciejewski, L.; Biot, C.; Georges, A. J.; Millet, P.; Antimicrob. Agents Chemother. 1998, 42, 540.         [ Links ]

4. Atteke, C.; Ndong, J. M. M.; Aubouy, A.; Maciejewski, L.; Brocard, J.; Lebibi, J.; Deloron, P. J.; Antimicrob. Chemother. 2003, 51, 1021.         [ Links ]

5. Blackie, M. A. L.; Chibale, K.; Met. Based Drugs 2008, 2008: ID 495123.         [ Links ]

6. Biot, C.; Delhaes, L.; Maciejewski, L. A.; Mortuaire, M.; Camus, D.; Dive, D.; Brocard, J. S.; Eur. J. Med. Chem. 2000, 35, 707.         [ Links ]

7. Torres, J. C.; Pilli, R. A.; Vargas, M. D.; Violante, F. A.; Garden, S. J.; Pinto, A. C.; Tetrahedron 2002, 58, 4487.         [ Links ]

8. Köpf-Maier, Köpf, H.; Neuse, E. W.; J. Cancer Res. Clin. Oncol. 1984, 108, 336.         [ Links ]

9. Osella, D.; Ferrali, M.; Zanello, P.; Laschi, F.; Fontani, M.; Nervi, C.; Cavigiolio, G.; Inorg. Chim. Acta 2000, 42, 306.         [ Links ]

10. Gopal, Y. N. V.; Jayaraju, D.; Kondapi, K.; Arch. Biochem. Biophys. 2000, 376, 229.         [ Links ]

11. Kondapi, A. K.; Satyanarayana, N.; Sai krishna, A.D.; Arch. Biochem. Biophys. 2006, 450, 123.         [ Links ]

12. Bramson, H. N.; Corona, J.; Davis, S. T.; Dickerson, S. H.; Edelstein, M.; Frye, S. V.; Gampe, R. T., Jr.; Harris, P. A.; Hassell, A.; Holmes, W. D.; Hunter, R. N.; Lackey, K. E.; Lovejoy, B.; Luzzio, M. J.; Montana, V.; Rocque, W. J.; Rusnak, D.; Shewchuk, L.; Veal, J. M.; Walker, D. H.; Kuyper, L. F.; J. Med. Chem. 2001, 44, 4339;         [ Links ] Bogoyevitch, M. A; Fairlie, D. P.; Drug Discov. Today 2007, 12, 622;         [ Links ] Cerchiaro, G.; Ferreira, A. M. C.; J. Braz. Chem. Soc. 2006, 17, 1473.         [ Links ]

13. Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T. Cui, J.; Fukuda, J. Y.; Chu, J-Y; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T. C.; Tang, F.; Wei, J. Tang., C.; J. Med. Chem. 2003, 46, 1116.         [ Links ]

14. Roskoski, R. Jr.; Biochem. Biophys. Res. Commun. 2007, 356, 323.         [ Links ]

15. Jayashankaran, J.; Durga, R.; Manian, R. S.; Raghunathan, R.; Synth. Commun. 2006, 36, 979;         [ Links ] Babu, A. R. S.; Raghunathan, R.; Tetrahedron Lett. 2008, 49, 4487.         [ Links ]

16. General experimental procedure: A mixture of oxindole (0.2 mmol), ferrocenecarboxyaldehyde (0.22 mmol), ethanol (5 mL) and 100 mg of KOH was allowed to stir at rt for 15 min (2) or under reflux for 1 h (3-10). The progress of the reactions was monitored by TLC. After total consumption of the substrate, the crude reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The E and Z products were separated by silica gel column chromatography (using hexane/ethyl acetate as eluent).

 

 

Received: July 15, 2008
Web Release Date: August 27, 2008
FAPESP helped in meeting the publication costs of this article.

 

 

* e-mail: barbara.iq@gmail.com

 

 

Supplementary Information

 

Clique aqui para ampliar

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License