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Substituted Chalcones and Flavones as Human Monoamine Oxidase A (hMAO‐A) Inhibitors with Prostate Cancer Antiproliferative Effects
Author(s) -
Zarmouh Najla O,
Gangapuram Madhavi,
Eyunni Suresh,
Elshami Faisel,
Redda Kinfe K,
Messeha Samia S,
Soliman Karam F
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.807.8
Subject(s) - monoamine oxidase , chalcone , chemistry , lncap , prostate cancer , clorgyline , flavones , monoamine oxidase b , stereochemistry , cancer , pharmacology , enzyme , biochemistry , medicine , chromatography
Aggressive prostate cancer (PCa) tumors exhibit an increased expression of monoamine oxidase A (MAOA). The use of MAO‐A inhibition as a strategy to treat PCa have not been adequately investigated. In the current investigation, we tested 22 of synthesized chalcone and flavone derivatives for their inhibition of recombinant human ( h ) MAO‐A activity and their anticancer effect in the PCa LNCaP. Our results showed that five of these derivatives inhibited h MAO‐A with an IC90 < 100 μM, 2‐(3,4,5‐trimethoxystyryl)‐3‐hydroxy‐5,7‐dimethoxy‐4H‐chromen‐4‐one (2a, 6%), 6,8‐dichloro‐3‐hydroxy‐2‐phenyl‐4H‐chromen‐4‐one (2b, 8%), (E)‐3‐(3,4‐dichlorophenyl)‐1‐(2‐hydroxy‐4,6‐dimethoxyphenyl)prop‐2‐en‐1‐one (2c, 9%), (E)‐1‐(3,5‐dichloro‐2‐hydroxyphenyl)‐3‐phenylprop‐2‐en‐1‐one (2d, 3%) and 6,7‐dichloro‐2‐phenyl‐4H‐chromen‐4‐one (2e, 3%), to be comparable to standard MAO‐AIs of pirlindole (4%) and clorgyline (2%). Furthermore, the IC 50 of the top compounds was 2e (IC 50 = 0.03 μM) to be the most potent among all the screened compounds on h MAO‐A. This compound was followed by 2a (IC 50 = 0.7 μM), 2d (IC 50 = 1.2 μM), 2c (IC 50 = 4.9 μM), 2d (IC 50 = 15.5 μM), respectively. In silico, docking scores were generated for the compounds under study using Open Eye's OEDocking Hybrid method. The highly active compound 2e scored high −7.21 (Chemgauss4 Score) compared to all other compounds under study at the active site of human MAO‐A crystal structure (PDB; 2Z5X). The effects of these five compounds on PCa cells were investigated using the resazurin fluorometric assay. At 20 μM Incubation for 72 h, 2a, 2b, 2c and 2d showed a significant LNCaP cells viability inhibition (P > 0.0001), while 2e was not effective. Compound 2d (IG 50 = 5.5 μM), 2b (IG 50 = 8.8 μM), and 2c (IG 50 = 9.5 μM) were the most potent antiproliferative compounds which were more effective than the standard MAO‐AIs pirlindole and clorgyline (IG 50 > 10 μM). The obtained data using 2b, 2c, 2d, and 2e chalcone and flavone derivatives suggest that MAOA has a potential as a therapeutic target in PCa. Support or Funding Information Supported by NIH Grants G12 MD007582 and P20 MD 006738