Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In Silico Molecular Docking, Synthesis of 4-(4-benzoylaminophenoxy) Phenol Derivatives as Androgen Receptor Antagonists

Author(s): Ramakrishnan Elancheran*, Senthamaraikannan Kabilan*, Jibon Kotoky, Muthiah Ramanathan and Atanu Bhattacharjee

Volume 22, Issue 5, 2019

Page: [307 - 316] Pages: 10

DOI: 10.2174/1386207322666190701124752

Price: $65

Abstract

Aim and Objective: To study the structural difference, optimization, molecular docking and development of new benzoyl amino phenoxy phenol derivatives as anti-prostate cancer agents.

Materials and Methods: Strategies towards the identification of novel benzoyl amino phenoxy phenol (BAPP), molecular docking was performed with the designed Androgen Receptor (AR) blockers. Pharmacophore-based studies revealed that the nitro- or cyano-substituted anilide groups have influenced the activity profiles of non-steroidal AR antagonists, followed by the molecular docking studies with five AR receptors. Molecular docking studies were carried out using Maestro from Schrödinger. Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the BAPP derivatives were evaluated for the predictive bioavailability/drug-likeness. These studies supported vital information for designing new anti-prostate cancer agents.

Results and Discussion: There are 125 compounds were screened and best fit compounds (12 entries) were well-synthesized in good to excellent yields and anticancer activities were evaluated. The compounds, 6i showed the highest activities of this series (14.65 ± 1.35 µM).

Conclusion: The present approach is simple and efficient for the synthesis of BAPP derivatives and the observed IC50 values of BAPPs were in good agreement with the glide scores obtained from the molecular docking. We, further, intend to carry out in vitro and in vivo AR binding studies for the active compounds.

Keywords: Androgen receptor, prostate cancer, AR antagonist, molecular docking, Benzoyl amino phenoxy phenol, antiprostate cancer agents.

« Previous Next »
[1]
Ferlay, J.; Shin, H.R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917. [http://dx.doi.org/10.1002/ijc.25516]. [PMID: 21351269].
[2]
Noone, A.M.; Miller, D.; Brest, A.; Yu, M.; Ruhl, J.; Tatalovich, Z.; Mariotto, A.; Lewis, D.R.; Chen, H.S.; Feuer, E.J.; Cronin, K.A. National Cancer Institute. Bethesda, MD,, https://seer.cancer.gov/csr/1975_2015/ [based on November 2017]; SEER data submission, posted to the SEER web site, April . 2018.
[3]
Elancheran, R.; Maruthanila, V.L.; Ramanathan, M.; Kabilan, S.; Devi, R.; Kunnumakkara, A.; Kotoky, J. Recent discoveries and developments of androgen receptor based therapy for prostate cancer. MedChemComm, 2015, 6, 746-768. [http://dx.doi.org/10.1039/C4MD00416G].
[4]
Kushwaha, N.; Saini, R.K.; Kushwaha, S.K.S. Synthesis of some Amide derivatives and their Biological activity. Synthesis, 2011, 3, 203-209.
[5]
Dolezal, M.; Miletin, M.; Kralova, K. substituted amides of pyrazine-2-carboxylic acids: Synthesis and biological activity. Molecules, 2002, 7, 363-373. [http://dx.doi.org/10.3390/70300363].
[6]
Aziz, M.A.; Serya, R.A.; Lasheen, D.S.; Abdel-Aziz, A.K.; Esmat, A.; Mansour, A.M.; Singab, A.N.B.; Abouzid, K.A. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci. Rep., 2016, 6, 24460. [http://dx.doi.org/10.1038/srep24460]. [PMID: 27080011].
[7]
Choi, H.E.; Shin, J.S.; Leem, D.G.; Kim, S.D.; Cho, W.J.; Lee, K.T. 6-(3,4-Dihydro-1H-isoquinoline-2-yl)-N-(6-methoxypyridine-2-yl) nicotinamide-26 (DIMN-26) decreases cell proliferation by induction of apoptosis and downregulation of androgen receptor signaling in human prostate cancer cells. Chem. Biol. Interact., 2016, 260, 196-207. [http://dx.doi.org/10.1016/j.cbi.2016.10.008]. [PMID: 27720946].
[8]
Ferla, S.; Bassetto, M.; Pertusati, F.; Kandil, S.; Westwell, A.D.; Brancale, A.; McGuigan, C. Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety. Bioorg. Med. Chem. Lett., 2016, 26(15), 3636-3640. [http://dx.doi.org/10.1016/j.bmcl.2016.06.001]. [PMID: 27301368].
[9]
Yamada, A.; Fujii, S.; Mori, S.; Kagechika, H. Design and synthesis of 4-(4-benzoylaminophenoxy)phenol derivatives as androgen receptor antagonists. ACS Med. Chem. Lett., 2013, 4(10), 937-941. [http://dx.doi.org/10.1021/ml4001744]. [PMID: 24900588].
[10]
Schrödinger, L.L.C. New York, NY , 2013.
[11]
Glide, version 6.1; Schrödinger, LLC: New York, NY, 2013.
[12]
Elancheran, R.; Saravanan, K.; Choudhury, B.; Divakar, S.; Kabilan, S.; Ramanathan, M.; Das, B.; Devi, R.; Kotoky, J. Design and development of oxobenzimidazoles as novel androgen receptor antagonists. Med. Chem. Res., 2016, 25, 539-552. [http://dx.doi.org/10.1007/s00044-016-1504-3].
[13]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749. [http://dx.doi.org/10.1021/jm0306430]. [PMID: 15027865].
[14]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47(7), 1750-1759. [http://dx.doi.org/10.1021/jm030644s]. [PMID: 15027866].
[15]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196. [http://dx.doi.org/10.1021/jm051256o]. [PMID: 17034125].
[16]
Zhang, X.H.; Huang, L.H.; Chen, S.; Qi, G.R. Improvement of thermal properties and flame retardancy of epoxy-amine thermosets by introducing bisphenol containing azomethine moiety. Express Polym. Lett., 2007, 1, 326-332. [http://dx.doi.org/10.3144/expresspolymlett.2007.46].
[17]
Ramadas, K.; Srinivasan, N. Iron-ammonium chloride-a convenient and inexpensive reductant. Synth. Commun., 1992, 22, 3189-3195. [http://dx.doi.org/10.1080/00397919208021132].
[18]
Valeur, E.; Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev., 2009, 38(2), 606-631. [http://dx.doi.org/10.1039/B701677H]. [PMID: 19169468].
[19]
Choudhury, B.; Kandimalla, R.; Elancheran, R.; Bharali, R.; Kotoky, J. Garcinia morella fruit, a promising source of antioxidant and anti-inflammatory agents induces breast cancer cell death via triggering apoptotic pathway. Biomed. Pharmacother., 2018, 103, 562-573. [http://dx.doi.org/10.1016/j.biopha.2018.04.068]. [PMID: 29677543].
[20]
Maruthanila, V.L.; Elancheran, R.; Roy, N.K.; Bhattacharya, A.; Kunnumakkara, A.B.; Kabilan, S.; Kotoky, J. In silico molecular modelling of selected natural ligands and their binding features with estrogen receptor alpha. Curr Comput Aided Drug Des, 2019, 15(1), 89-96. [http://dx.doi.org/10.2174/1573409914666181008165356]. [PMID: 30306879].
[21]
Lakshmithendral, K.; Saravanan, K.; Elancheran, R.; Archana, K.; Manikandan, N.; Arjun, H.A.; Ramanathan, M.; Lokanath, N.K.; Kabilan, S. Design, synthesis and biological evaluation of 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives as anti-breast cancer agents. Eur. J. Med. Chem., 2019, 168, 1-10. [http://dx.doi.org/10.1016/j.ejmech.2019.02.033]. [PMID: 30798049].
[22]
Maruthanila, V.L.; Elancheran, R.; Kunnumakkar, A.B.; Kabilan, S.; Kotoky, J. Pleiotropic Effect of mahanine and girinimbine analogs: anticancer mechanism and its therapeutic versatility. Anticancer. Agents Med. Chem., 2018, 18(14), 1983-1990. [http://dx.doi.org/10.2174/1871520618666180830151720]. [PMID: 30173653].
[23]
Elancheran, R.; Saravanan, K.; Divakar, S.; Kumari, S.; Maruthanila, V.L.; Kabilan, S.; Ramanathan, M.; Devi, R.; Kotoky, J. Design, synthesis and biological evaluation of novel 1, 3- thiazolidine-2, 4-diones as anti-prostate cancer agents. Anticancer. Agents Med. Chem., 2017, 17(13), 1756-1768. [PMID: 28403781].
[24]
Divakar, S.; Saravanan, K.; Karthikeyan, P.; Elancheran, R.; Kabilan, S.; Balasubramanian, K.K.; Devi, R.; Kotoky, J.; Ramanathan, M. Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway. Chem. Biol. Interact., 2017, 275, 22-34. [http://dx.doi.org/10.1016/j.cbi.2017.07.023]. [PMID: 28757136].
[25]
Saravanan, K.; Elancheran, R.; Divakar, S.; Anand, S.A.; Ramanathan, M.; Kotoky, J.; Lokanath, N.K.; Kabilan, S. Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents. Bioorg. Med. Chem. Lett., 2017, 27(5), 1199-1204. [http://dx.doi.org/10.1016/j.bmcl.2017.01.065]. [PMID: 28162857].
[26]
Ramadas, K.; Srinivasan, N. Iron-ammonium chloride-a convenient and inexpensive reductant. Synth. Commun., 1992, 22(22), 3189-3195. [http://dx.doi.org/10.1080/00397919208021132].
[27]
Kolczewski, S.; Roche, O.; Steward, L.; Wichmann, J.; Woltering, T. Hoffmann-La Roche Inc, 6-substituted benzoxazines. U.S. Patent 8,163,740.24 2012.

Rights & Permissions Print Cite
Article Metrics
48
6
1
1
© 2024 Bentham Science Publishers | Privacy Policy