Limits...
Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

Vannini F, Chattopadhyay M, Kodela R, Rao PP, Kashfi K - Redox Biol (2015)

Bottom Line: We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells.The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis.These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States.

No MeSH data available.


Related in: MedlinePlus

Docking of positional isomers of NOSH-ASA to the active site of cyclooxygenase-1. Hydrogen atoms are not shown for clarity. Polar and nonpolar interactions are colored coded and details are provided in text.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556775&req=5

f0020: Docking of positional isomers of NOSH-ASA to the active site of cyclooxygenase-1. Hydrogen atoms are not shown for clarity. Polar and nonpolar interactions are colored coded and details are provided in text.

Mentions: The binding interactions of o-NOSH-ASA with COX-1 enzyme shows that it binds in the COX-1 active site in an open U-shaped conformation (Fig. 4, panel A) and underwent contacts with most of the residues that line the binding site. The 5-phenyl-3H-1,2-dithiole-3-thione substituent ortho to the (nitrooxybutanoyloxy)benzoate group was in a hydrophobic region consisting of Val349, Leu352, Phe381, Tyr385, Trp387, Phe518, Ile523 and Gly526. The 1,2-dithiole-3-thione moiety was oriented closer to the catalytic site at the apex of COX-1 active site and underwent van der Waal's contact with side chains of Leu352 and Ile523 respectively (π-alkyl interaction, distance<5 Å). Hydrophobic π-sulfur interactions were seen with the disulfide sulfurs and aromatic rings of Phe381 and Trp387 (distance<5 Å). The 5-phenyl ring attached to 1,2-dithiole-3-thione moiety was in van der Waal's contact with side chains of Val349 and Ala527 (distance<5 Å). The benzoate ring with (nitrooxy)butanoyloxy substituent was oriented closer to the entrance of COX-1 active site and was surrounded by Leu93, Met113, Val116, Arg120, Val349, Leu531, and Tyr355. The benzoate C=O (COO) linked to 5-phenyl ring underwent electrostatic interaction with the guanidine side chain of Arg120 (distance<3.0 Å) whereas the benzoate aromatic ring underwent T-shaped π–π interaction with aromatic ring of Tyr355 (distance<5 Å). Moving the 5-phenyl-3H-1,2-dithiole-3-thione substituent from ortho to meta-position in m-NOSH-ASA had a dramatic effect on its binding mode within COX-1 compared to o-NOSH-ASA and exhibits an l-shaped conformation (Fig. 4, panel B). The 1,2-dithiole-3-thione moiety was oriented closer to the entrance of COX-1 active site in a nonpolar region comprised of Met113, Val116, Tyr355 and Leu359. The sulfur atom (dithiole ring) underwent π-sulfur and π–π hydrophobic interaction with Tyr355 (distance<5 Å). In addition, π-sulfur interaction was seen with Met113 (distance<5 Å). The 5-phenyl ring next to 1,2-dithiole-3-thione was in van der Waal's contact with side chains of Val349, Ile523 and Ala527 (distance<5 Å). The benzoate ring was oriented closer to the apex of COX-1 active site (distance<5 Å). Interestingly, the charged nitrooxy group (ON+OO−) underwent cation-π interaction with aromatic ring of Phe209 (distance<4 Å). The binding interactions of p-NOSH-ASA shows that it binds in a closed U-shaped conformation such that the 1,2-dithiole-3-thione was oriented closer to the apex of COX-1 binding site (Phe381, Leu384, Tyr385 and Trp387) as seen with the o-NOSH-ASA (Fig. 4, panel C). The 1,2-dithiole-3-thione underwent π-sulfur interactions with Phe381 and Trp387 (distance<5.5 Å). The 5-phenyl ring linked to 1,2-dithiole-3-thione moiety underwent a number of van der Waal's contact with side chains of Val349, Leu352, Ile523 and Ala527 (distance<5 Å). Similar to o-NOSH-ASA the benzoate ring was oriented closer to the entrance of COX-1 active site and underwent hydrophobic contacts with Met113 and Val116. The benzoate C=O (COO) linked to 5-phenyl ring underwent hydrogen bonding interaction with Arg120 and Tyr355 (distance<3 Å). However unlike o-NOSH-ASA, the (nitrooxy)butanoyloxy substituent in p-NOSH-ASA was not in proximity to the COX-1 entrance. Instead it was closer to Ser530 and Leu531 (distance<3 Å). Interestingly the nitrooxy group (ON+OO−) underwent polar contact with OH of Ser530 (distance=2.7 Å), the acetylation site of aspirin [24]. These investigations show that positional isomers o-, m-, p-NOSH-ASA exhibit different binding modes in the COX-1 active site. In this regard, the orientation of 5-membered 1,2-dithiole-3-thione for regioisomers o-NOSH-ASA and p-NOSH-ASA was similar to the methylthiazole substituent present in meloxicam which suggests that lipophilic, planar 5-membered rings could orient closer to Phe381, Tyr385 and Trp387 at the apex of COX-1 enzyme [18].


Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

Vannini F, Chattopadhyay M, Kodela R, Rao PP, Kashfi K - Redox Biol (2015)

Docking of positional isomers of NOSH-ASA to the active site of cyclooxygenase-1. Hydrogen atoms are not shown for clarity. Polar and nonpolar interactions are colored coded and details are provided in text.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556775&req=5

f0020: Docking of positional isomers of NOSH-ASA to the active site of cyclooxygenase-1. Hydrogen atoms are not shown for clarity. Polar and nonpolar interactions are colored coded and details are provided in text.
Mentions: The binding interactions of o-NOSH-ASA with COX-1 enzyme shows that it binds in the COX-1 active site in an open U-shaped conformation (Fig. 4, panel A) and underwent contacts with most of the residues that line the binding site. The 5-phenyl-3H-1,2-dithiole-3-thione substituent ortho to the (nitrooxybutanoyloxy)benzoate group was in a hydrophobic region consisting of Val349, Leu352, Phe381, Tyr385, Trp387, Phe518, Ile523 and Gly526. The 1,2-dithiole-3-thione moiety was oriented closer to the catalytic site at the apex of COX-1 active site and underwent van der Waal's contact with side chains of Leu352 and Ile523 respectively (π-alkyl interaction, distance<5 Å). Hydrophobic π-sulfur interactions were seen with the disulfide sulfurs and aromatic rings of Phe381 and Trp387 (distance<5 Å). The 5-phenyl ring attached to 1,2-dithiole-3-thione moiety was in van der Waal's contact with side chains of Val349 and Ala527 (distance<5 Å). The benzoate ring with (nitrooxy)butanoyloxy substituent was oriented closer to the entrance of COX-1 active site and was surrounded by Leu93, Met113, Val116, Arg120, Val349, Leu531, and Tyr355. The benzoate C=O (COO) linked to 5-phenyl ring underwent electrostatic interaction with the guanidine side chain of Arg120 (distance<3.0 Å) whereas the benzoate aromatic ring underwent T-shaped π–π interaction with aromatic ring of Tyr355 (distance<5 Å). Moving the 5-phenyl-3H-1,2-dithiole-3-thione substituent from ortho to meta-position in m-NOSH-ASA had a dramatic effect on its binding mode within COX-1 compared to o-NOSH-ASA and exhibits an l-shaped conformation (Fig. 4, panel B). The 1,2-dithiole-3-thione moiety was oriented closer to the entrance of COX-1 active site in a nonpolar region comprised of Met113, Val116, Tyr355 and Leu359. The sulfur atom (dithiole ring) underwent π-sulfur and π–π hydrophobic interaction with Tyr355 (distance<5 Å). In addition, π-sulfur interaction was seen with Met113 (distance<5 Å). The 5-phenyl ring next to 1,2-dithiole-3-thione was in van der Waal's contact with side chains of Val349, Ile523 and Ala527 (distance<5 Å). The benzoate ring was oriented closer to the apex of COX-1 active site (distance<5 Å). Interestingly, the charged nitrooxy group (ON+OO−) underwent cation-π interaction with aromatic ring of Phe209 (distance<4 Å). The binding interactions of p-NOSH-ASA shows that it binds in a closed U-shaped conformation such that the 1,2-dithiole-3-thione was oriented closer to the apex of COX-1 binding site (Phe381, Leu384, Tyr385 and Trp387) as seen with the o-NOSH-ASA (Fig. 4, panel C). The 1,2-dithiole-3-thione underwent π-sulfur interactions with Phe381 and Trp387 (distance<5.5 Å). The 5-phenyl ring linked to 1,2-dithiole-3-thione moiety underwent a number of van der Waal's contact with side chains of Val349, Leu352, Ile523 and Ala527 (distance<5 Å). Similar to o-NOSH-ASA the benzoate ring was oriented closer to the entrance of COX-1 active site and underwent hydrophobic contacts with Met113 and Val116. The benzoate C=O (COO) linked to 5-phenyl ring underwent hydrogen bonding interaction with Arg120 and Tyr355 (distance<3 Å). However unlike o-NOSH-ASA, the (nitrooxy)butanoyloxy substituent in p-NOSH-ASA was not in proximity to the COX-1 entrance. Instead it was closer to Ser530 and Leu531 (distance<3 Å). Interestingly the nitrooxy group (ON+OO−) underwent polar contact with OH of Ser530 (distance=2.7 Å), the acetylation site of aspirin [24]. These investigations show that positional isomers o-, m-, p-NOSH-ASA exhibit different binding modes in the COX-1 active site. In this regard, the orientation of 5-membered 1,2-dithiole-3-thione for regioisomers o-NOSH-ASA and p-NOSH-ASA was similar to the methylthiazole substituent present in meloxicam which suggests that lipophilic, planar 5-membered rings could orient closer to Phe381, Tyr385 and Trp387 at the apex of COX-1 enzyme [18].

Bottom Line: We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells.The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis.These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States.

No MeSH data available.


Related in: MedlinePlus