Skip to main content

Advertisement

Log in

Ferrozoles: Ferrocenyl derivatives of letrozole with dual effects as potent aromatase inhibitors and cytostatic agents

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

In the treatment of hormone-dependent cancers, aromatase inhibitors (AI) are receiving increased attention due to some undesirable effects such as the risk of endometrial cancer and thromboembolism of SERMs (selective estrogen receptor modulators). Letrozole is the most active AI with 99% aromatase inhibition. Unfortunately, this compound also exhibits some adverse effects such as hot flashes and fibromyalgias. Therefore, there is an urgent need to explore new types of AIs that retain the same—or even increased—antitumor ability. Inspired by the letrozole structure, a set of new derivatives has been synthesized that include a ferrocenyl moiety and different heterocycles. The derivative that contains a benzimidazole ring, namely compound 6, exhibits a higher aromatase inhibitory activity than letrozole and it also shows potent cytostatic behavior when compared to other well-established aromatase inhibitors, as demonstrated by dose–response, cell cycle, apoptosis and time course experiments. Furthermore, 6 promotes the inhibition of cell growth in both an aromatase-dependent and -independent fashion, as indicated by the study of A549 and MCF7 cell lines. Molecular docking and molecular dynamics calculations on the interaction of 6 or letrozole with the aromatase binding site revealed that the ferrocene moiety increases the van der Waals and hydrophobic interactions, thus resulting in an increase in binding affinity. Furthermore, the iron atom of the ferrocene fragment can form a metal-acceptor interaction with a propionate fragment, and this results in a stronger coupling with the heme group—a possibility that is consistent with the strong aromatase inhibition of 6.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

References

  1. Jin-zi J, Ke-jing L, Jie H et al (2014) Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay. Acta Pharmacol Sin 35:1082–1092. https://doi.org/10.1038/aps.2014.51

    Article  CAS  Google Scholar 

  2. Chen H, Yan M, Shi W et al (2019) Expression of estrogen receptor beta and overall survival in non-small cell lung cancer patients: protocol for a systematic review and meta-analysis of cohort studies. Med (United States) 98:1–4. https://doi.org/10.1097/MD.0000000000017559

    Article  Google Scholar 

  3. Rahal BA, Bardaweel SK (2022) Implications and efficacy of aromatase inhibitors in combination and monotherapy for the treatment of lung cancer. Anticancer Agents Med Chem 22:3114–3124. https://doi.org/10.2174/1871520622666220426112435

    Article  CAS  PubMed  Google Scholar 

  4. Langdon SP, Herrington CS, Hollis RL, Gourley C (2020) Estrogen signaling and its potential as a target for therapy in ovarian cancer. Cancers (Basel) 12:1647. https://doi.org/10.3390/cancers12061647. (17 pages)

    Article  CAS  PubMed  Google Scholar 

  5. Sainsbury R (2013) The development of endocrine therapy for women with breast cancer. Cancer Treat Rev 39:507–517. https://doi.org/10.1016/j.ctrv.2012.07.006

    Article  CAS  PubMed  Google Scholar 

  6. Hong Y, Li H, Yuan YC, Chen S (2010) Sequence-function correlation of aromatase and its interaction with reductase. J Steroid Biochem Mol Biol 118:203–206. https://doi.org/10.1016/j.jsbmb.2009.11.010

    Article  CAS  PubMed  Google Scholar 

  7. Brueggemeier RW, Hackett JC, Diaz-Cruz ES (2005) Aromatase inhibitors in the treatment of breast cancer. Endocr Rev 26:331–345. https://doi.org/10.1210/er.2004-0015

    Article  CAS  PubMed  Google Scholar 

  8. Santen RJ, Brodie H, Simpson ER et al (2009) History of aromatase: Saga of an important biological mediator and therapeutic target. Endocr Rev 30:343–375. https://doi.org/10.1210/er.2008-0016

    Article  CAS  PubMed  Google Scholar 

  9. Buzdar A, Howell A (2001) Advances in aromatase inhibition: Clinical efficacy and tolerability in the treatment of breast cancer. Clin Cancer Res 7:2620–2635

    CAS  PubMed  Google Scholar 

  10. Ahmad I, Shagufta, (2015) Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer. Eur J Med Chem 102:375–386. https://doi.org/10.1016/j.ejmech.2015.08.010

    Article  CAS  PubMed  Google Scholar 

  11. Brueggemeier RW (2006) Update on the use of aromatase inhibitors in breast cancer. Expert Opin Pharmacother 7:1919–1930. https://doi.org/10.1517/14656566.7.14.1919

    Article  CAS  PubMed  Google Scholar 

  12. Nabholtz JM, Mouret-Reynier MA, Durando X et al (2009) Comparative review of anastrozole, letrozole and exemestane in the management of early breast cancer. Expert Opin Pharmacother 10:1435–1447. https://doi.org/10.1517/14656560902953738

    Article  CAS  PubMed  Google Scholar 

  13. Mouridsen H, Gershanovich M, Sun Y et al (2001) Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the international letrozole breast cancer group. J Clin Oncol 19:2596–2606. https://doi.org/10.1200/JCO.2001.19.10.2596

    Article  CAS  PubMed  Google Scholar 

  14. Campos SM (2004) Aromatase inhibitors for breast cancer in postmenopausal women. Oncologist 9:126–136. https://doi.org/10.1634/theoncologist.9-2-126

    Article  CAS  PubMed  Google Scholar 

  15. Lang M, Batzl C, Furet P et al (1993) Structure-activity relationships and binding model of novel aromatase inhibitors. J Steroid Biochem Mol Biol 44:421–428. https://doi.org/10.1016/0960-0760(93)90245-R

    Article  CAS  PubMed  Google Scholar 

  16. Bhatnagar AS, Häusler A, Schieweck K et al (1990) Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Molec Biol 37:1021–1027. https://doi.org/10.1016/0960-0760(90)90460-3

    Article  CAS  PubMed  Google Scholar 

  17. Geisler J (2011) Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole- of clinical importance. Br J Cancer 104:1059–1066. https://doi.org/10.1038/bjc.2011.58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Løning PE, Eikesdal HP (2013) Aromatase inhibition 2013: Clinical state of the art and questions that remain to be solved. Endocr Relat Cancer 20:R183–R201. https://doi.org/10.1530/ERC-13-0099

    Article  CAS  Google Scholar 

  19. Waks AG, Wines EP (2019) Breast cancer treatment: a review. J Am Med Assoc 321:288–300

    Article  CAS  Google Scholar 

  20. Cortez VA, Suzuki T, Miyat N et al (2011) Abstract 1733: therapeutic significance of ERα—PELP1 axis in blocking endocrine therapy resistance. Cancer Res 71:1733. https://doi.org/10.1158/1538-7445.AM2011-1733

    Article  Google Scholar 

  21. Doiron J, Soultan AH, Richard R et al (2011) Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors. Eur J Med Chem 46:4010–4024. https://doi.org/10.1016/j.ejmech.2011.05.074

    Article  CAS  PubMed  Google Scholar 

  22. Woo LWL, Wood PM, Bubert C et al (2013) Synthesis and structure-activity relationship studies of derivatives of the dual aromatase-sulfatase inhibitor 4-{[(4-Cyanophenyl)(4H–1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate. ChemMedChem 8:779–799. https://doi.org/10.1002/cmdc.201300015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Song Z, Liu Y, Dai Z et al (2016) Synthesis and aromatase inhibitory evaluation of 4-N-nitrophenyl substituted amino-4H-1,2,4-triazole derivatives. Bioorganic Med Chem 24:4723–4730. https://doi.org/10.1016/j.bmc.2016.08.014

    Article  CAS  Google Scholar 

  24. Wood PM, Woo LWL, Labrosse JR et al (2008) Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity. J Med Chem 51:4226–4238. https://doi.org/10.1021/jm800168s

    Article  CAS  PubMed  Google Scholar 

  25. Lézé MP, Le Borgne M, Pinson P et al (2006) Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl)methyl]- 1H-indoles: potent and selective aromatase inhibitors. Bioorganic Med Chem Lett 16:1134–1137. https://doi.org/10.1016/j.bmcl.2005.11.099

    Article  CAS  Google Scholar 

  26. Dai Y, Xiao Y, Wang Q et al (2014) Syntheses and QSAR studies of benzylimidazole derivatives and benzylcarbazole as potential aromatase inhibitors. Asian J Chem 26:2381–2388

    Article  CAS  Google Scholar 

  27. Kang H, Xiao X, Huang C et al (2018) Potent aromatase inhibitors and molecular mechanism of inhibitory action. Eur J Med Chem 143:426–437. https://doi.org/10.1016/j.ejmech.2017.11.057

    Article  CAS  PubMed  Google Scholar 

  28. Kalalinia F, Jouya M, Komachali AK et al (2018) Design, synthesis, and biological evaluation of new azole derivatives as potent aromatase inhibitors with potential effects against breast cancer. Anticancer Agents Med Chem 18:1016–1024. https://doi.org/10.2174/1871520618666180116105858

    Article  CAS  PubMed  Google Scholar 

  29. Wang R, Shi HF, Zhao JF et al (2013) Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives. Bioorganic Med Chem Lett 23:1760–1762. https://doi.org/10.1016/j.bmcl.2013.01.045

    Article  CAS  Google Scholar 

  30. Lézé MP, Palusczak A, Hartmann RW, Le Borgne M (2008) Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors. Bioorganic Med Chem Lett 18:4713–4715. https://doi.org/10.1016/j.bmcl.2008.06.094

    Article  CAS  Google Scholar 

  31. Pedini M, Alunni Bistocchi G, De Meo G et al (1999) New heterocyclic derivatives of benzimidazole with germicidal activity: part XIII. In vitro aromatase inhibitory activity; preliminary observations. Farmaco 54:327–330. https://doi.org/10.1016/S0014-827X(99)00018-X

    Article  CAS  Google Scholar 

  32. Toshiyuki M, Kato M, Sasahara H et al (2000) Synthesis and antitumor activity of benzimidazolyl-1,3,5-triazine and benzimidazolylpyrimidine derivatives. Chem Pharm Bull 48:1778–1781

    Article  Google Scholar 

  33. Acar Çevik U, Sağlık BN, Osmaniye D et al (2020) Synthesis and docking study of benzimidazole–triazolothiadiazine hybrids as aromatase inhibitors. Arch Pharm (Weinheim) 353:e2000008. https://doi.org/10.1002/ardp.202000008

    Article  CAS  PubMed  Google Scholar 

  34. Sağlık BN, Şen AM, Evren AE et al (2020) Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors. Z Naturforsch C J Biosci 75:353–362. https://doi.org/10.1515/znc-2020-0104

    Article  CAS  PubMed  Google Scholar 

  35. Di Matteo M, Ammazzalorso A, Andreoli F et al (2016) Synthesis and biological characterization of 3-(imidazol-1-ylmethyl)piperidine sulfonamides as aromatase inhibitors. Bioorganic Med Chem Lett 26:3192–3194. https://doi.org/10.1016/j.bmcl.2016.04.078

    Article  CAS  Google Scholar 

  36. Pouget C, Yahiaoui S, Fagnere C et al (2004) Synthesis and biological evaluation of 4-imidazolylflavans as nonsteroidal aromatase inhibitors. Bioorg Chem 32:494–503. https://doi.org/10.1016/j.bioorg.2004.06.008

    Article  CAS  PubMed  Google Scholar 

  37. Yahiaoui S, Pouget C, Buxeraud J et al (2011) Lead optimization of 4-imidazolylflavans: New promising aromatase inhibitors. Eur J Med Chem 46:2541–2545. https://doi.org/10.1016/j.ejmech.2011.03.043

    Article  CAS  PubMed  Google Scholar 

  38. Yahiaoui S, Pouget C, Fagnere C et al (2004) Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors. Bioorganic Med Chem Lett 14:5215–5218. https://doi.org/10.1016/j.bmcl.2004.07.090

    Article  CAS  Google Scholar 

  39. Wood PM, Woo LWL, Thomas MP et al (2011) Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates. ChemMedChem 6:1423–1438. https://doi.org/10.1002/cmdc.201100145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Woo LWL, Bubert C, Purohit A, Potter BVL (2011) Hybrid dual aromatase-steroid sulfatase inhibitors with exquisite picomolar inhibitory activity. ACS Med Chem Lett 2:243–247. https://doi.org/10.1021/ml100273k

    Article  CAS  PubMed  Google Scholar 

  41. Gilardi G, Di Nardo G (2017) Heme iron centers in cytochrome P450: structure and catalytic activity. Rend Lincei 28:S159–S167. https://doi.org/10.1007/s12210-016-0565-z

    Article  Google Scholar 

  42. Adhikari N, Amin SA, Jha T, Gayen S (2017) Integrating regression and classification-based QSARs with molecular docking analyses to explore the structure-antiaromatase activity relationships of letrozole-based analogs. Can J Chem 95:1285–1295. https://doi.org/10.1139/cjc-2017-0419

    Article  CAS  Google Scholar 

  43. Siden Top, Tang J, Vessieres A, et al (1996) Ferrocenyl hydroxytamoxifen: a prototype for a new range of oestradiol receptor site-directed cytotoxics. Chem Commun, pp 955–956

  44. Top S, Vessières A, Leclercq G et al (2003) 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-depen. Chem A Eur J 9:5223–5236. https://doi.org/10.1002/chem.200305024

    Article  CAS  Google Scholar 

  45. Jaouen G, Vessières A, Top S (2015) Ferrocifen type anti cancer drugs. Chem Soc Rev 44:8802–8817. https://doi.org/10.1039/c5cs00486a

    Article  CAS  PubMed  Google Scholar 

  46. Ornelas C (2011) Application of ferrocene and its derivatives in cancer research. New J Chem 35:1973–1985. https://doi.org/10.1039/c1nj20172g

    Article  CAS  Google Scholar 

  47. Krasovskiy A, Knochel P (2004) A LiCl-mediated Br/Mg exchange reaction for the preparation of functionalized aryl- and heteroarylmagnesium compounds from organic bromides. Angew Chemie - Int Ed 43:3333–3336. https://doi.org/10.1002/anie.200454084

    Article  CAS  Google Scholar 

  48. Neshvad G, Roberts RMG, Silver J (1982) Mössbauer studies in ferrocene complexes. IV. Substituent effects in ferrocenyl-carbenium ions. J Organomet Chem 236:237–244

    Article  CAS  Google Scholar 

  49. Saberi MR, Vinh TK, Yee SW et al (2006) Potent CYP19 (Aromatase) 1-[(Benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole Inhibitors: synthesis and biological evaluation Mohammed. J Med Chem 19:1016–1022

    Article  Google Scholar 

  50. Desiraju GR, Steiner TT (2001) The weak hydrogen bond. Oxford University Press, Berlin

    Book  Google Scholar 

  51. Arunan E, Desiraju GR, Klein RA et al (2011) Definition of the hydrogen bond (IUPAC Recommendations 2011). Pure Appl Chem 83:1637–1641. https://doi.org/10.1351/PAC-REC-10-01-02

    Article  CAS  Google Scholar 

  52. Mautner MM (2005) The ionic hydrogen bond. Chem Rev 105:213–284. https://doi.org/10.1021/cr9411785

    Article  CAS  Google Scholar 

  53. Durá G, Carrión MC, Jalón FA et al (2014) Metal supramolecular frameworks with silver and ditopic Bis(pyrazolyl)methane ligands: effect of the anions and ligand substitution. Cryst Growth Des 14:3510–3529. https://doi.org/10.1021/cg5004484

    Article  CAS  Google Scholar 

  54. Carrión MC, Durá G, Jalón FA et al (2012) Polynuclear complexes containing ditopic bispyrazolylmethane ligands. Influence of metal geometry and supramolecular interactions. Cryst Growth Des 12:1952–1969. https://doi.org/10.1021/cg201677s

    Article  CAS  Google Scholar 

  55. Weinberg OK, Marquez-Garban DC, Fishbein MC et al (2005) Aromatase inhibitors in human lung cancer therapy. Cancer Res 65:11287–11291. https://doi.org/10.1158/0008-5472.CAN-05-2737

    Article  CAS  PubMed  Google Scholar 

  56. Zhou D, Wang J, Chen E et al (1993) Aromatase GENE is amplified in MCF-7 human breast cancer cells. J Steroid Biochem Molec Biol 46:147–153

    Article  CAS  PubMed  Google Scholar 

  57. VanArsdale T, Boshoff C, Arndt KT, Abraham RT (2015) Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment. Clin Cancer Res 21:2905–2910. https://doi.org/10.1158/1078-0432.CCR-14-0816

    Article  CAS  PubMed  Google Scholar 

  58. https://www.rcsb.org/structure/3EQM. Accessed 21 Jan 2020

  59. Zhang W, Ramamoorthy Y, Kilicarslan T et al (2002) Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab Dispos 30:314–318. https://doi.org/10.1124/dmd.30.3.314

    Article  CAS  PubMed  Google Scholar 

  60. Jones JP, Joswig-Jones CA, Hebner M et al (2011) The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1. Chem Biol Interact 193:50–56. https://doi.org/10.1016/j.cbi.2011.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cumming H, Rücker C (2017) Octanol-water partition coefficient measurement by a simple 1H NMR method. ACS Omega 2:6244–6249. https://doi.org/10.1021/acsomega.7b01102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Palm K, Stenberg P, Luthman K, Artursson P (1997) Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm Res 14:568–571

    Article  CAS  PubMed  Google Scholar 

  63. Ghosh A, Vishveshwara S (2007) A study of communication pathways in methionyl-tRNA synthetase by molecular dynamics simulations and structure network analysis. Proc Natl Acad Sci U S A 104:15711–15716. https://doi.org/10.1073/pnas.0704459104

    Article  PubMed  PubMed Central  Google Scholar 

  64. SAINT v8.37, Bruker-AXS (2016) APEX3 v2016.1.0. Madison, Wisconsin, USA.

  65. Krause L, Herbst-Irmer R, SADABS et al (2015) SADABS. J Appl Crystallogr 48:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Farrugia LJ (2012) WinGX and ORTEP for Windows: an update. J Appl Cryst 45:849–854. https://doi.org/10.1107/S0021889812029111

    Article  CAS  Google Scholar 

  67. Sheldrick GM (2014) SHELX-2014, Progr. Cryst. Struct. Refinement, Univ Göttingen, Göttingen, Ger

  68. Morris GM, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Krieger E, Darden T, Nabuurs SB et al (2004) Making optimal use of empirical energy functions: force-field parameterization in crystal space. Proteins Struct Funct Bioinforma 57:678–683. https://doi.org/10.1002/prot.20251

    Article  CAS  Google Scholar 

  70. Krieger E, Koraimann G, Vriend G (2002) Increasing the precision of comparative models with YASARA NOVA—a self-parameterizing force field. Proteins Struct Funct Genet 47:393–402. https://doi.org/10.1002/prot.10104

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER), Grant PID2021-127187OB-C21 to BRM, MCIN/AEI/10.13039/501100011033, Grant PID2021-122222OB-I00 “ERDF A way of making Europe” to RSP, Junta de Comunidades de Castilla-La Mancha-FEDER (JCCM) (Grants SBPLY/19/180501/000260 to BRM and SBPLY/19/180501/000251 to JLA), and UCLM-FEDER (Grants 2019-GRIN-27183, 2019-GRIN-27209, 2020-GRIN-29093 to FAJ and 2021-GRIN-31118 to JLA). Funds from Fundación Leticia Castillejo Castillo (2021-AYUDA-32401) to RSP and MJRH are also acknowledged. RSP and MJRH’s Research Institute and the work carried out in their laboratory, received partial support from the European Community through the FEDER. CG wants to acknowledge his fellowship to both the European Social Fund and Plan Propio of I+D+I of UCLM (2022-PRED-20649). GD thanks the Junta de Comunidades de Castilla la Mancha and EU for financial support through the European Regional Development Fund (project SBPLY/19/180501/000191).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Blanca R. Manzano.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 2212 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diaz de Greñu, B., Fernández-Aroca, D.M., Organero, J.A. et al. Ferrozoles: Ferrocenyl derivatives of letrozole with dual effects as potent aromatase inhibitors and cytostatic agents. J Biol Inorg Chem 28, 531–547 (2023). https://doi.org/10.1007/s00775-023-02006-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-023-02006-0

Keywords

Navigation