Advertisement

Journal of Chemical Biology

, Volume 10, Issue 2, pp 69–84 | Cite as

Design and synthesis of a new steroid-macrocyclic derivative with biological activity

  • Maria López-Ramos
  • Lauro Figueroa-Valverde
  • Socorro Herrera-Meza
  • Marcela Rosas-Nexticapa
  • Francisco Díaz-Cedillo
  • Elodia García-Cervera
  • Eduardo Pool-Gómez
  • Regina Cahuich-Carrillo
Original Article
  • 196 Downloads

Abstract

The aims of this study were to evaluate the positive inotropic effect of a new macrocyclic derivative (compound 11) and characterize the molecular mechanism involved in its biological activity. The first step was achieved by synthesis of a macrocyclic derivative involving a series of reactions for the preparation of several steroid derivatives such as (a) steroid-pyrimidinone (3 and 4), (b) steroid-amino (5), (c) steroid-imino (6), (d) ester-steroid (7 and 8), and (e) amido-steroid (9 and 10). Finally, 11 was prepared by removing the tert-butyldimethylsilane fragment of 10. The biological activity of compounds on perfusion pressure and vascular resistance was evaluated on isolated rat heart using the Langendorff model. The inotropic activity of 11 was evaluated in presence of prazosin, metoprolol, indomethacin, nifedipine, and flutamide to characterize its molecular mechanism. Theoretical experiments were carried out with a Docking model, to assess potential interactions of androgen receptor with 11. The results showed that only this macrocyclic derivative exerts changes on perfusion pressure and vascular resistance translated as the positive inotropic effect, and this effect was blocked with flutamide; these data indicate that the positive inotropic activity induced by this macrocyclic derivative was via androgen receptor activation. The theoretical results indicated that the interaction of the macrocyclic derivative with the androgen receptor involves several amino acid residues such as Leu704, Asn705, Met780, Cys784, Met749, Leu762, Phe764, Ser778, and Met787. In conclusion, all these data suggest that the positive inotropic activity of the macrocyclic derivative may depend on its chemical structure.

Keywords

Testosterone Cycloheptadecaphane Inotropic activity Steroid Macrocyclic 

Notes

Compliance with ethical standards

The experimental methods used in this investigation were reviewed and approved by the Animal Care and Use Committee of University Autonomous of Campeche (no. PI-420/12) and were in accordance with the guide for the care and use of laboratory animals [10]. Male Wistar rats, weighing 200–250 g, were obtained from University Autonomous of Campeche.

References

  1. 1.
    Kolbeck R, LaNeave C, Aguirre A, Nosek T, Pannel K (1992) Inotropic influence of macrocyclic polyethers on tracheal smooth muscle. Pharmacol Biochem Behavior 42:645–650CrossRefGoogle Scholar
  2. 2.
    Trevisi L, Bova S, Cargnelli G, Danieli-Betto D, Floreani M, Germinario E, D’Auria M, Luciani S (2000) Callipeltin-A, a cyclic depsipeptide inhibitor of the cardiac sodium-calcium exchanger and positive inotropic agent. Biochem Biophys Res Comm 279:219–222CrossRefGoogle Scholar
  3. 3.
    Watanabe H, Chiba S (1982) Cardiac stimulating effects of macrocyclic polyamines. Japan J Pharmacol 32:394–396CrossRefGoogle Scholar
  4. 4.
    Idée J, Berthommier C, Goulas V, Corot C, Santus R, Hermine C, Schaefer M, Bonnemai B (1998) Haemodynamic effects of macrocyclic and linear gadolinium chelates in rats: role of calcium and transmetallation. Biometals 11:113–112CrossRefGoogle Scholar
  5. 5.
    Bogatskii A, Luk’yanenko N, Savenko T, Vongai V, Nazarov E, Tsymbal I (1984) Effect of the macrocyclic polyester 15-crown-5 on ionic permeability of excitable membranes. Bull Exp Biol Med 98(98):1045–1048CrossRefGoogle Scholar
  6. 6.
    Miyamoto S, Izumi M, Hori M, Kobayashi M, Ozaki H, Karaki H (2000) Xestospongin C, a selective and membrane-permeable inhibitor of IP3 receptor, attenuates the positive inotropic effect of α-adrenergic stimulation in guinea-pig papillary muscle. British J Pharmacol 130:650–654CrossRefGoogle Scholar
  7. 7.
    Kolbeck R, Hendry L, Bransome E, Speir W (1980) Crown ethers which influence cardiac and respiratory muscle contractility. Experientia 40:727–731CrossRefGoogle Scholar
  8. 8.
    Lunardi C, DaSilva R, Bendhack L (2009) New nitric oxide donors based on ruthenium complexes. Brazilian J Med Biol Res 42:87–93CrossRefGoogle Scholar
  9. 9.
    Figueroa-Valverde L, Díaz-Cedillo F, García-Cervera E, Pool-Gómez E, López-Ramos M, Rosas-Nexticapa M, Hau-Heredia L, Sarabia-Alcocer B (2015) Synthesis and antibacterial activity evaluation of two androgen derivatives. Steroids 93:8–15CrossRefGoogle Scholar
  10. 10.
    Bayne K (1996) Revised guide for the care and use of laboratory animals available. Am Physiol Soc 39:208–211Google Scholar
  11. 11.
    Garcia-Cervera E, Figueroa-Valverde L, Díaz-Cedillo F, López-Ramos M, Rosas-Nexticapa M, Pool-Gómez E, Jarquin-Barberena H, Rodriguez-Hurtado M, Chan-Salvador M (2011) Design and synthesis of a new pirrol-indol derivative with positive inotropic activity. Oriental J Chem 31:31–41Google Scholar
  12. 12.
    Sarabia-Alcocer B, Figueroa-Valverde L, Díaz-Cedillo F, Hau-Heredia L, Rosas-Nexticapa M, Garcia-Cervera E, Pool-Gómez E, Garcia-Martinez R (2014) Activity induced by a naphthalene-prazosin derivative on ischemia/reperfusion injury in rats. Pharmacol Pharm 5:1130–1142CrossRefGoogle Scholar
  13. 13.
    Hocht C, Opezzo J, Gorzalczany S, Bramuglia G, Tiara C (1997) Una aproximación cinética y dinámica de metildopa en ratas con coartación aórtica mediante microdiálisis. Rev Argentina Cardiol 67:769–773Google Scholar
  14. 14.
    Bikadi Z, Hazai E (2009) Application of the PM6 semiempirical method to modeling proteins enhances docking accuracy of AutoDock. J Cheminform 1–16Google Scholar
  15. 15.
    Halgren T (1999) MMFF VI. MMFF94s option for energy minimization studies. J Comput Chem 20:720–729CrossRefGoogle Scholar
  16. 16.
    Morris M, Goodsell D, Hallyday R, Huey R, Hart W, Belew R, Olson A (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662CrossRefGoogle Scholar
  17. 17.
    Solis F (1981) Minimization by random search techniques. Mathem Meth Oper Res 19–30.Google Scholar
  18. 18.
    Liebscher J, Hartmann H (1982) Synthese und Abwandlung N-substituierter 2(1 H)-Pyrimidin-thione-Ein einfacher Zugang zu Pyrimidino[2,3-b]1,3,4-thiadiazoliumsalzen. Adv Syn Catal 324:942–946Google Scholar
  19. 19.
    Önal Z, Korkusuz E, İlhan I (2010) Cyclization reactions of l-pyrimidinyl-3-arylthiourea derivatives with oxalyl dichloride. Heter Comm 16:79–84Google Scholar
  20. 20.
    Yu A, Sharanin V, Shestopalov V, Nesterov V, Litvinov P, Mortikov Y, Promonenkov V, Shklover V, Struchkov Y (1987) Cyclization reactions of nitriles. 26. Synthesis, structure, and properties of 2-amino-4-methylthio-5-cyano-6(1H)-pyrimidinethione. Chem Heter Comp 23:1105–1112CrossRefGoogle Scholar
  21. 21.
    Zigeuner G, Frank A, Adam A (1970) Reaction of dihydro-6-methyl-4-phenyl-2(1H)-pyrimidinthione with formaldehyde and amines. (heterocyclic compounds, XXVIII). Monats für Chem 101:1788–1793CrossRefGoogle Scholar
  22. 22.
    Parish A, Gilliom R, Purcell W, Browne R, Spirk R, White H (1982) Syntheses and diuretic activity of 1,2-dihydro-2-(3-pyridyl)-3H-pyrido[2,3-d]pyrimidin-4-one and related compounds. J Med Chem 25:98–102CrossRefGoogle Scholar
  23. 23.
    Shawali A, Abdallah M, Mosslhe A, Farghaly T (2000) A facile one-pot regioselective synthesis of [1,2,4]triazolo[4,3-a]5(1H)-pyrimidinones via tandem Japp-Klingemann, Smiles rearrangement, and cyclization reactions. Heteroatom Chem 13:136–140CrossRefGoogle Scholar
  24. 24.
    Shirayev A, Moiseev I, Karpeev S (2005) Synthesis and cis/trans isomerism of N-alkyl-1,3-oxathiolane-2-imines. Arkivok iv: 199–207Google Scholar
  25. 25.
    Uppiah D, Bhowon D, Jhaumeer M (2009) Synthesis of imines derived from diphenyldisulphide diamine or p-vanillin. E-J. Chem l: S195–200, 2009Google Scholar
  26. 26.
    Figueroa-Valverde L, Díaz-Cedillo F, García-Cervera E, Rosas-Nexticapan M, Ramos-López M (2013) Design and synthesis of naphthol derivative. Asian J Chem 25:6724–6726Google Scholar
  27. 27.
    Clark R, Graham W, Winter A (1925) The catalytic preparation of ether from alcohol by means of aluminum oxide. J Am Chem Soc 47:2748–2754CrossRefGoogle Scholar
  28. 28.
    Ravi E, Byun H, Wang S, Bittman R (1994) Preparation of ether-linked 2-acetamido-2-deoxy β-glycolipids via zinc chloride promoted coupling of Ac4GlcNAcCl with lipid hydroxy groups. Tetrahedron Lett 35:505–508CrossRefGoogle Scholar
  29. 29.
    Takekoshi T (1987) Synthesis of high performance aromatic polymers via nucleophilic nitro displacement reaction. Polymer J 19:191–202CrossRefGoogle Scholar
  30. 30.
    Figueroa-Valverde L, Díaz-Cedillo F, Rosas-Nexticapa M, García-Cervera E, Pool-Gomez E, Barberena H, Lopez-Ramos M, Rodriguez-Hurtado F, Chan-Salvador M (2015) Design and synthesis of some carbamazepine derivatives using several strategies. Lett Org Chem 12:394–401CrossRefGoogle Scholar
  31. 31.
    Saxon E, Armstrong E, Bertozzi J (2000) Traceless Staudinger ligation for the chemoselective synthesis of amide bonds. Org Lett 2:2141–2143CrossRefGoogle Scholar
  32. 32.
    Masala S, Taddei M Solid-supported chloro[1,3,5]triazine. A versatile new synthetic auxiliary for the synthesis of amide libraries. Org Lett 1: 1355–1357Google Scholar
  33. 33.
    Figueroa-Valverde L, Díaz-Cedillo F, Ceballos-Reyes G (2006) Synthesis of pregnenolone-pregnenolone dimer via ring A-ring a connection. J Mex Chem Soc 50:42–45Google Scholar
  34. 34.
    Ogawa Y, Shibasaki M (1984) Selective removal of tetrahydropyranyl ethers in the presence of t-butyldimethylsilyl ethers. Tetrahedron Lett 25:663–664CrossRefGoogle Scholar
  35. 35.
    Wilson N, Keay B (1996) A mild palladium(II) catalyzed desilylation of phenolic t-butyldimethylsilyl ethers. Tetrahedron Lett 37:153–156CrossRefGoogle Scholar
  36. 36.
    Newton R, Reynolds D, Finch M, Kelly D, Roberts D (1979) An excellent reagent for the removal of the t-butyldimethylsilyl protecting group. Tetrahedron Lett 20:398–3982CrossRefGoogle Scholar
  37. 37.
    Idée J, Berthommier C, Goulas V, Corot C, Santus R, Hermine C, Schaefer M, Bonnemain B (1998) Haemodynamic effects of macrocyclic and linear gadolinium chelates in rats: role of calcium and transmetallation. Biometals 11:113–123CrossRefGoogle Scholar
  38. 38.
    Parker J, Waite M, Pettit G, Daniel L (1988) Stimulation of arachidonic acid release and prostaglandin synthesis by bryostatin. Carcinogenesis 9:1471–1474CrossRefGoogle Scholar
  39. 39.
    Watanabe H, Chiba S (1982) Cardiac stimulating effects of macrocyclic polyamines. Japanese J Pharmacol 32:394–396CrossRefGoogle Scholar
  40. 40.
    Hu Z, Zhang D, Wang D, Sun B, Safoor A, Young C, Lou H, Yuan H (2015) Bisbibenzyls, novel proteasome inhibitors, suppress androgen receptor transcriptional activity and expression accompanied by activation of autophagy in prostate cancer LNCaP cells. Pharm Biol 54:364–374CrossRefGoogle Scholar
  41. 41.
    Thiemermann C, Bowes J, Myint F, Vane J (2012) Inhibition of the activity of poly(ADP ribose) synthetase reduces ischemia–reperfusion injury in the heart and skeletal muscle. Proc Natl Acad Sci 94:679–683CrossRefGoogle Scholar
  42. 42.
    Levine P, Imberg K, Garabedian M, Kirshenbaum K (2012) Multivalent peptidomimetic conjugates: a versatile platform for modulating androgen receptor activity. J Am Chem Soc 134:6912–6915CrossRefGoogle Scholar
  43. 43.
    Calleja C, Pascussi J, Mani J, Maurel P, Vilarem M (1998) The antibiotic rifampicin is a nonsteroidal ligand and activator of the human glucocorticoid receptor. Nat Med 4:92–96CrossRefGoogle Scholar
  44. 44.
    Liu R, Perez J, Liang D, Saven J (2012) Binding site and affinity prediction of general anesthetics to protein targets using docking. Anesth Analg 114:947–955CrossRefGoogle Scholar
  45. 45.
    Rosales M, Correa J (2015) The importance of employing computational resources for the automation of drug discovery. Expert Opinion Drug Dis 10:213–219CrossRefGoogle Scholar
  46. 46.
    Askew E, Gampe R, Stanley T, Faggart J, Wilson E (2007) Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J Biol Chem 282:25801–25816CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Maria López-Ramos
    • 1
  • Lauro Figueroa-Valverde
    • 1
  • Socorro Herrera-Meza
    • 2
  • Marcela Rosas-Nexticapa
    • 3
  • Francisco Díaz-Cedillo
    • 4
  • Elodia García-Cervera
    • 1
  • Eduardo Pool-Gómez
    • 1
  • Regina Cahuich-Carrillo
    • 1
  1. 1.Laboratory of PharmacochemistryUniversity Autonomous of CampecheCampecheMexico
  2. 2.Instituto de Investigaciones PsicológicasUniversidad VeracruzanaXalapaMexico
  3. 3.Facultad de NutriciónUniversidad VeracruzanaXalapaMexico
  4. 4.Escuela Nacional de Ciencias BiológicasInstituto Politécnico NacionalSanto TomasMexico

Personalised recommendations