QSAR analysis of some azole derivatives as potent aromatase inhibitors
A high proportion of breast tumors are hormone-dependent, implying that endogenous estrogens play a critical role in cancer cell proliferation. One of the most effective strategies for the treatment of breast cancer is reduction of estrogens level by inhibiting aromatase enzyme which is responsible for catalyzing the rate-limiting step in estrogen biosynthesis. A series of azole derivatives as potential aromatase inhibitors were subjected to two different drug design methodologies, QSAR and molecular docking simulation. MLR, FA-MLR, PCR and GA-PLS were employed to make connections between the structural parameters and aromatase inhibitory activity. GA-PLS represented superior results and a model with a high statistical quality (R2 = 0.86 and Q2 = 0.83) for predicting the inhibitory activity. The results can provide useful information for the development of more potent aromatase inhibitors.
A. R. Ortiz, M. Pastor, A. Palomer, G. Cruciani, F. Gago, R. C. Wade, 'Reliability of comparative molecular field analysis models: effects of data scaling and variable selection using a set of human synovial fluid phospholipase A2 inhibitors', J. Med. Chem 1997, 40, 1136-1148.
A. R. Ortiz, M. T. Pisabarro, F. Gago, R. C. Wade, 'Prediction of drug binding affinities by comparative binding energy analysis', J. Med. Chem 1995, 38, 2681-2691.
C. Bennion, S. Connolly, N. P. Gensmantel, C. Hallam, C. G. Jackson, W. U. Primrose, et al. 'Design and synthesis of some substrate analog inhibitors of phospholipase A2 and investigations by NMR and molecular modeling into the binding interactions in the enzyme-inhibitor complex', J. Med. Chem 1992, 35, 2939-2951.
A. R. Ortiz, M. T. Pisabarro, J. Gallego, F. Gago. 'Implications of a consensus recognition site for phosphatidylcholine separate from the active site in cobra venom phospholipases A2', Biochem 1992, 31, 2887-2896.
R. B. Sessions, P. Dauber‐Osguuthorpe, M. M. Campbell, D. J. Osguthorpe, 'Modeling of substrate and inhibitor binding to phospholipase A2', Proteins: Structure, Function, and Bioinformatics 1992, 14, 45-64.
J. P. Noel, C. A. Bingman, T. Deng, C. M. Dupureur, K. J. Hamilton, R. T. Jiang, et al. 'Phospholipase A2 engineering. X-ray structural and functional evidence for the interaction of lysine-56 with substrates', Biochem 1991, 30, 11801-11811.
S. Chumsri, T. Howes, T. Bao, G. Sabnis, A. Brodie, 'Aromatase, aromatase inhibitors, and breast cancer', J Steroid Biochem Mol Biol 2011, 125,13-22.
Y. Hong, S. Chen, 'Aromatase inhibitors: structural features and biochemical characterization', Ann N Y Acad Sci 2006, 1089, 237-251.
G. E. Séralini, S. Moslemi, 'Aromatase inhibitors: past, present and future', Mol Cell Endocrinol 2001, 178, 117-131.
W. O. Foye, T. L. Lemke, D. A. Williams, 'Foye's principles of medicinal chemistry', Lippincott Williams & Wilkins 2008.
W. R. Miller, J. Bartlett, A. M. Brodie, R. W. Brueggemeier, E. D. Salle, P. E. Lønning, et al. 'Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter?', The oncologist 2008, 13, 829-837.
J. Narashimamurthy, A. R. R. Rao, G. N. Sastry, 'Aromatase inhibitors: a new paradigm in breast cancer treatment', Curr Med Chem Anti-Cancer Agents 2004, 4, 523-534.
J. M. Beale, J. Block, R. Hill, 'Organic medicinal and pharmaceutical chemistry', Lippincott Williams & Wilkins Philadelphia 2010.
O. Deeb, B. W. Clare, 'QSAR of aromatic substances: protein tyrosine kinase inhibitory activity of flavonoid analogues', Chem Biol drug des 2007, 70, 437-449.
R. G. Brereton, 'Applied chemometrics for scientists', John Wiley & Sons 2007.
K. Baumann, 'Cross-validation as the objective function for variable-selection techniques', TrAC Trends Anal Chem 2003, 22, 395-406.
M. R. Yadav, P. M. Sabale, R. Giridhar, C. Zimmer, J. Haupenthal, R. W. Hartmann, 'Synthesis of some novel androstanes as potential aromatase inhibitors', Steroids 2011, 76, 464-470.
M. Takahashi, K. Yamashita, M. Numazawa, 'Probing the binding pocket of the active site of aromatase with 2-phenylaliphatic androsta-1, 4-diene-3, 17-dione steroids', Steroids 2010, 75, 330-337.
M. Recanatini, A. Bisi, A. Cavalli, F. Belluti, S. Gobbi, A. Rampa, et al. 'A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17α-hydroxylase/C17, 20-lyase', J Med Chem 2001, 44, 672-680.
T. K. Vinh, S. W. Yee, A. J. Kirby, P. J. Nicholls, C. Simons, '1‐[(Benzofuran‐2‐yl) phenylmethyl] triazoles as steroidogenic inhibitors: synthesis and in vitro inhibition of human placental CYP19 aromatase', Anti-cancer drug Des 2001, 16, 217-225.
R. Whomsley, E. Fernandez, P. Nicholls, H. Smith, P. Lombardi, V. Pestellini, 'Substituted 1-[(benzofuran-2-yl)-phenylmethyl]-imidazoles as potent inhibitors of aromatase in vitro and in female rats in vivo', J Steroid Biochem Mol Biol 1993, 44, 675-676.
D. A. Nagib, D. W. MacMillan, 'Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis', Nature 2011, 480, 224-228.
S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, 'Fluorine in medicinal chemistry', Chem Soc Rev 2008, 37, 320-330.
O. A. Tomashenko, V. V. Grushin, 'Aromatic trifluoromethylation with metal complexes', Chem Rev 2011; 111, 4475-4521.
W. K. Hagmann, 'The many roles for fluorine in medicinal chemistry', J Med Chem 2008, 51, 4359-4369.
R. Todeschini, 'Milano chemometrics and QSPR Group',2008.
S. Castellano, G. Stefancich, R. Ragno, K. Schewe, M. Santoriello, A. Caroli, et al. 'CYP19 (aromatase): exploring the scaffold flexibility for novel selective inhibitors', Bioorg Med Chem 2008, 16, 8349-8358.
R. Wang, H. F. Shi, J. F. Zhao, Y. P. He, H. B. Zhang, J.P. Liu, 'Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives', Bioorg Med Chem Lett 2013, 23,1760-1762.
L. L. Woo, O. B. Sutcliffe, C. Bubert, A. Grasso, S. K. Chander, A. Purohit, et al. 'First dual aromatase-steroid sulfatase inhibitors', J Med Chem 2003, 46, 3193-3196.
S. Gobbi, A. Cavalli, M. Negri, K. E. Schewe, F. Belluti, L. Piazzi, et al. 'Imidazolylmethylbenzophenones as highly potent aromatase inhibitors', J Med Chem 2007, 50, 3420-3422.
S. Yahiaoui, C. Pouget, J. Buxeraud, A. J. Chulia, C. Fagnère, 'Lead optimization of 4-imidazolylflavans: New promising aromatase inhibitors', Eur J Med Chem 2011, 46, 2541-2545.
P. Sonnet, P. Dallemagne, J. Guillon, C. Enguehard, S. Stiebing, J. Tanguy, et al. 'New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives', Bioorg Med Chem 2000, 8, 945-955.
S. Gobbi, C. Zimmer, F. Belluti, A. Rampa, R. W. Hartmann, M. Recanatini, et al. 'Novel highly potent and selective nonsteroidal aromatase inhibitors: synthesis, biological evaluation and structure− activity relationships investigation', J Med Chem 2010, 53, 5347-5351.
S. Nagar, M. A. Islam, S. Das, A. Mukherjee, A. Saha, 'Pharmacophore mapping of flavone derivatives for aromatase inhibition', Molec Divers 2008, 12, 65-76.
M. R. Saberi, T. K. Vinh, S. W. Yee, B. N. Griffiths, P. J. Evans, C. Simons, 'Potent CYP19 (aromatase) 1-[(benzofuran-2-yl)(phenylmethyl) pyridine,-imidazole, and-triazole inhibitors: synthesis and biological evaluation', J Med Chem 2006, 49, 1016-1022.
C. Pouget, S. Yahiaoui, C. Fagnere, G. Habrioux, A. J. Chulia, 'Synthesis and biological evaluation of 4-imidazolylflavans as nonsteroidal aromatase inhibitors', Bioorg Chem 2004, 32, 494-503.
M. P. Lézé, M. L. Borgne, P. Pinson, A. Palusczak, M. Duflos, G. L. Baut, et al. 'Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl) methyl]-1H-indoles: potent and selective aromatase inhibitors', Bioorg Med Chem Lett 2006, 16, 1134-1137.
J. C. Hackett, Y. W. Kim, B. Su, R. W. Brueggemeier, 'Synthesis and characterization of azole isoflavone inhibitors of aromatase', Bioorg Med Chem 2005, 13, 4063-4070.
S. Yahiaoui, C. Pouget, C. Fagnere, Y. Champavier, G. Habrioux, A. J. Chulia, 'Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors', Bioorg Med Chem Lett 2004, 14, 5215-5218.
M. P. Lézé, A. Palusczak, R. W. Hartmann, M. L. Borgne, 'Synthesis of 6-or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors', Bioorg Med Chem Lett 2008, 18, 4713-4715.
A. Karjalainen, A. Kalapudas, M. Södervall, O. Pelkonen, R. Lammintausta, 'Synthesis of new potent and selective aromatase inhibitors based on long-chained diarylalkylimidazole and diarylalkyltriazole molecule skeletons', Eur J Pharm Sci 2000, 11, 109-131.
L. L. Woo, C. Bubert, O. B. Sutcliffe, A. Smith, S. K. Chander, M. F. Mahon, et al. 'Dual aromatase-steroid sulfatase inhibitors', J Med Chem 2007, 50, 3540-3560.
R. W. Kennard, L. A. Stone, 'Computer Aided Design of Experiments', Technometrics 1969, 11, 137-148.
P. Bhattacharya, K. Roy, 'QSAR of adenosine A3 receptor antagonist 1, 2, 4-triazolo [4, 3-a] quinoxalin-1-one derivatives using chemometric tools', Bioorg Med Chem Lett 2005, 15, 3737-3743.
R. Leardi, 'Genetic algorithms in chemometrics and chemistry: a review', J Chemometrics 2001, 15, 559-569.
B. Hemmateenejad, 'Optimal QSAR analysis of the carcinogenic activity of drugs by correlation ranking and genetic algorithm-based PCR', J Chemometrics 2004, 18, 475-485.
R. Franke, A. Gruska, H. Waterbeemd, 'Chemometrics Methods in molecular design'. Methods and Principles in Medicinal Chemistry 1995, 2, 113-119.
H. Kubinyi, 'The quantitative analysis of structure-activity relationships'. w Wolff, M.(red.), Burger’s Chemistry and Drug Discovery. John Wiley & Sons Inc., New York 1995.
M. Olah, C. Bologa, T. I. Oprea, 'An automated PLS search for biologically relevant QSAR descriptors', J Comput Aided Mol Des 2004, 18, 437-449.
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution 3.0 License.
- Trends in Pharmaceutical Sciences, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, IR, Iran.
Tel/Fax: +98 71 32424128 Ext: 297
- P.O. Box: 17345-1583 Shiraz, Iran
- Web site: tips.sums.ac.ir
- pISSN: 2423-3722 eISSN: 2423-5652