Skip to main content

Advertisement

Log in

Synthesis, structure, and estrogenic activity of 2- and 3-substituted 2,3-dihydro-4H-1-benzopyran-4-ones

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Molecules with potent estrogenic activity are ~270 Å3 hydrophobic structures that encompass two hydroxyls among which is at least one phenol. However, compounds with only one phenol or devoid of such a ring have been shown to enhance ERα-mediated transcription at concentrations much larger than those measured with E2. In this context, we show here that benzopyrans sharing one hydroxyl/methoxyl and containing an additional benzylidenyl or a spirocyclohexyl motif are able to induce ERE-dependent transcription in breast carcinoma cells.

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.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Scheme 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Al Nakib T, Bezjak V, Meegan MJ, Chandy R (1990) Synthesis and antifungal activity of some 3-benzylidenechroman-4-ones and 2-benzylidene-1-tetralones. Eur J Med Chem 25:455–462

    Article  CAS  Google Scholar 

  • Aronica SM, Katzenellenbogen BS (1991) Progesterone receptor regulation in uterine cells: stimulation by estrogen, cyclic adenosine 3′,5′-monophosphate, and insulin-like growth factor I and suppression by antiestrogens and protein kinase inhibitors. Endocrinology 128:2045–2052

    Article  PubMed  CAS  Google Scholar 

  • Bennett P, Donnelly JA, Meaney DC, O’Boyle P (1972) Stereochemistry of cyclopropyl ketones from the reaction of dimethylsulfoxonium methylide with 3-benzylidenechroman-4-ones. J Chem Soc Perkin I:1554–1559

    Article  Google Scholar 

  • Bergmann R, Gericke R (1990) Synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyrans and related compounds, new potassium channel activators. J Med Chem 33:492–504

    Article  PubMed  CAS  Google Scholar 

  • Biju AT, Wurz NE, Glorius F (2010) N-heterocyclic carbene-catalyzed cascade reaction involving the hydroacylation of unactivated alkynes. J Am Chem Soc 132:5970–5971

    Article  PubMed  CAS  Google Scholar 

  • Brandenburg K, Berndt M (1999) Diamond. Crystal Impact GbR, Bonn

    Google Scholar 

  • Demirpence E, Duchesne MJ, Badia E, Gagne D, Pons M (1993) MVLN cells: a bioluminescent MCE-7-derived cell line to study the modulation of estrogenic activity. J Steroid Biochem Mol Biol 46:355–364

    Article  PubMed  CAS  Google Scholar 

  • Dike SY, Merchant JR, Sapre NY (1991) A new and efficient general method for the synthesis of 2-spirobenzopyrans: first synthesis of cyclic analogues of precocene I and related compounds. Tetrahedron 47:4775–4786

    Article  CAS  Google Scholar 

  • Farkas L, Gottsegen Á, Nógrádi M, Strelisky J (1971) Synthesis of homoisoflavones—II: constituents of Eucomis autumnalis and E. punctata. Tetrahedron 27:5049–5054

    Article  CAS  Google Scholar 

  • Fisera L, Jarosková L, Lévai A, Jarosková E, Tóth G, Poláková M (1997) 1,3-dipolar cycloaddition of 3-arylidenechromanone-1-thiochromanone and -flavanone: regio- and stereoselective formation of spiroheterocycles. Heterocycles 45:1651–1655

    Article  CAS  Google Scholar 

  • Gallo D, Jacquot Y, Cleeren A, Jacquemotte F, Laïos I, Laurent G, Leclercq G (2007) Molecular basis of agonistic activity of ERα17p, a synthetic peptide corresponding to a sequence located at the N-terminal part of the estrogen receptor α ligand binding domain. Lett Drug Design Discov 4:346–355

    Article  CAS  Google Scholar 

  • Gee AC, Carlson KE, Martini PGV, Katzenellenbogen BS, Katzenellenbogen JA (1999) Coactivator peptides have a differential stabilizing effect on the binding of estrogens and antiestrogens with the estrogen receptor. Mol Endocrinol 13:1912–1923

    Article  PubMed  CAS  Google Scholar 

  • Gust R, Keilitz R, Schmidt K (2001) Investigations of new lead structures for the design of selective estrogen receptor modulators. J Med Chem 44:1963–1970

    Article  PubMed  CAS  Google Scholar 

  • Gust R, Keilitz R, Schmidt K (2002) Synthesis structural evaluation, and estrogen receptor interaction of 2,3-diarylpiperazines. J Med Chem 45:2325–2337

    Article  PubMed  CAS  Google Scholar 

  • Hassner A, Mead TC (1964) The stereochemistry of 2-benzalcyclohexanones and 2-benzalcyclopentanones. Tetrahedron 20:2201–2210

    Article  CAS  Google Scholar 

  • Hoshino Y, Tanaka H, Takeno N (1998) Regioselective reduction of the homoisoflavone system with dialkylboranes in the presence of palladium catalysts. Bull Chem Soc Jpn 71:2923–2928

    Article  CAS  Google Scholar 

  • Jacquot Y, Bermont L, Giorgi H, Refouvelet B, Adessi GL, Daubrosse E, Xicluna A (2001) Substituted benzopyranobenzothiazinones. Synthesis and estrogenic activity on MCF-7 breast carcinoma cells. Eur J Med Chem 36:127–136

    Article  PubMed  CAS  Google Scholar 

  • Jacquot Y, Cleeren A, Laïos I, Ma Y, Boulahdour A, Bermont L, Refouvelet B, Adessi G, Leclercq G, Xicluna A (2002) Pharmacological profile of 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones, a novel estrogen receptor agonist. Biol Pharm Bull 25:335–341

    Article  PubMed  CAS  Google Scholar 

  • Jacquot Y, Rojas C, Refouvelet B, Robert JF, Leclercq G, Xicluna A (2003) Recent advances in the development of phytoestrogens and derivatives: an update of the promising perspectives in the prevention of postmenopausal diseases. Mini-Rev Med Chem 3:387–400

    Article  PubMed  CAS  Google Scholar 

  • Jacquot Y, Laïos I, Cleeren A, Nonclercq D, Bermont L, Refouvelet B, Boubekeur K, Xicluna A, Leclercq G, Laurent G (2007) Synthesis, structure, and estrogenic activity of 4-amino-3-(2-methylbenzyl)coumarins on human breast carcinoma cells. Bioorg Med Chem 15:2269–2282

    Article  PubMed  CAS  Google Scholar 

  • Journe F, Chaboteaux C, Dumon JC, Leclercq G, Laurent G, Body JJ (2004) Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells. Br J Cancer 91:1703–1710

    PubMed  CAS  Google Scholar 

  • Kabbe HJ (1978) Eine einfache synthese von 4-chromanonen. Synthesis 12:886–889

    Article  Google Scholar 

  • Koorbanally NA, Crouch NR, Harilal A, Pillay B, Mulholland DA (2006) Coincident isolation of a novel homoisoflavonoid from Resnova humifusa and Eucomis montana (Hyacinthoideae: Hyacinthaceae). Biochem Sys Ecol 34:114–118

    Article  CAS  Google Scholar 

  • Kuiper GGJM, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JÅ (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 139:4252–4263

    Article  PubMed  CAS  Google Scholar 

  • Laïos I, Cleeren A, Leclercq G, Nonclercq D, Laurent G, Schlenk M, Wellner A, Gust R (2007) Effects of (R,S)/(S,R)-4,5-bis(2-chloro-4-hydroxyphenyl)-2-imidazolines and (R,S)/(S,R)-2,3-bis(2-chloro-4-hydroxyphenyl)piperazines on estrogen receptor alpha level and transcriptional activity in MCF-7 cells. Biochem Pharmacol 74:1029–1038

    Article  PubMed  Google Scholar 

  • Leclercq G, Gallo D, Cossy J, Laïos I, Larismont D, Laurent G, Jacquot Y (2011) Peptides targeting estrogen receptor alpha—potential applications for breast cancer treatment. Curr Pharm Design 17:2632–2653

    Article  CAS  Google Scholar 

  • Lévai A, Schág JB (1979) Synthesis of 3-benzylidenechroman-4-ones and 1-thiochroman-4-ones. Pharmazie 34:749

    Google Scholar 

  • Lévai A, Dinya Z, Schág JB, Tóth G, Szöllösy Á (1981) Synthesis of 3-benzyl-4-chromones and 3-benzyl-1-thio-4-chromones. Pharmazie 36:465–466

    Google Scholar 

  • Lévai A, Nemes C, Patonay T (1999) Synthesis of new (Z)-3-arylidenechromanones by the photoisomerization of (E)-3-arylidenechromanones. Heterocycl Commun 5:441–443

    Google Scholar 

  • Lóránd T, Vigh E, Garai J (2010) Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens. Curr Med Chem 17:3542–3574

    Article  PubMed  Google Scholar 

  • Maaroufi Y, Leclercq G (1994) Importance of A/B and C domains of the estrogen receptor for its adsorption to hydroxylapatite. J Steroid Biochem Mol Biol 48:155–163

    Article  PubMed  CAS  Google Scholar 

  • Manas ES, Xu ZB, Unwalla RJ, Somers WS (2004) Understanding the selectivity of genistein for human estrogen receptor-beta using X-ray crystallography and computational methods. Structure 12:2197–2207

    Article  PubMed  CAS  Google Scholar 

  • Miksicek RJ (1994) Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor. J Steroid Biochem Mol Biol 49:153–160

    Article  PubMed  CAS  Google Scholar 

  • Moore TW, Mayne GC, Katzenellenbogen JA (2010) Minireview: not picking pockets: nuclear receptor alternate-site modulators (NRAMs). Mol Endocrinol 24:683–695

    Article  PubMed  CAS  Google Scholar 

  • Mulvagh D, Meegan MJ, Donnelly D (1979) Rearrangements of 3-benzylidenechroman-4-ones. J Chem Res S 137

  • Panteleon V, Kostakis IK, Marakos P, Pouli N, Andreadou I (2008) Synthesis and free radical scavenging activity of some new spiropyranocoumarins. Bioorg Med Chem Lett 18:5781–5784

    Article  PubMed  CAS  Google Scholar 

  • Pons M, Gagne D, Nicolas JC, Mehtalli M (1990) A new cellular model of response to estrogens: a bioluminescent test to characterize anti(estrogen) molecules. Biotechniques 9:450–459

    PubMed  CAS  Google Scholar 

  • Seo HS, DeNardo DG, Jacquot Y, Laïos I, Salazar Vidal D, Zambrana CR, Leclercq G, Brown PH (2006) Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat 99:121–134

    Article  PubMed  CAS  Google Scholar 

  • Sheldrick GM (1986) SHELXS-86, computer program for structure solution. University of Gottingen, Gottingen

    Google Scholar 

  • Sheldrick GM (1997) SHELXL-97, computer program for structure refinement. University of Gottingen, Gottingen

    Google Scholar 

  • Subramaniyan G, Raghunathan R, Nethaji M (2002) A facile entry into a new class of spiroheterocycles: synthesis of dispiro[oxindolechromanone/flavanone/tetralone]pyrroloisoquinoline ring systems. Tetrahedron 58:9075–9079

    Article  CAS  Google Scholar 

  • von Rauch M, Schlenk M, Gust R (2004) Effects of C2-alkylation, N-alkylation, and N,N′-dialkylation on the stability and estrogen receptor interaction of (4R,5S)/(4S/5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines. J Med Chem 47:915–927

    Article  Google Scholar 

  • von Rauch M, Busch S, Gust R (2005) Investigations on the effects of basic side chains on the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imdazolines. J. J Med Chem 48:466–474

    Article  Google Scholar 

  • Wurtz JM, Egner U, Heinrich N, Moras D, Mueller-Fahrnow A (1998) Three-dimensional models of estrogen receptor binding domain complexes, based on related crystal structures and mutational and structure-activity relationship data. J Med Chem 41:1803–1814

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by grants from La Ligue Nationale contre le Cancer (comité de Montbéliard) and the Fonds J.C. Heuson de Cancérologie Mammaire. We are very grateful to Denis Lesage (UMR 7201, the Université Pierre et Marie Curie, Paris6) for mass spectrometry experiments. We are also grateful to Kamal Boubekeur of the Laboratoire de Chimie Inorganique et Matériaux Moléculaires, CNRS UMR 7071 (Université Pierre et Marie Curie, Paris6) for X-ray experiments; and to Olivier Lequin for 2D NMR experiments. Further, we are grateful to Dominique Gallo, Ioanna Laios, and Anny Cleeren for their precious participation in the biological assays.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yves Jacquot.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacquot, Y., Byrne, C., Xicluna, A. et al. Synthesis, structure, and estrogenic activity of 2- and 3-substituted 2,3-dihydro-4H-1-benzopyran-4-ones. Med Chem Res 22, 681–691 (2013). https://doi.org/10.1007/s00044-012-0058-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-012-0058-2

Keywords

Navigation