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Isolation of CFTR and TMEM16A inhibitors from Neorautanenia mitis (A. Rich) Verdcourt: Potential lead compounds for treatment of secretory diarrhea

Journal Article


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Abstract


  • © 2020 Elsevier Ltd A phytochemical study on the root extracts of Neorautanenia mitis, a Nigerian medicinal plant used in the management of diarrhea, led to the isolation of one new and 19 known natural products. These compounds and crude extracts were evaluated for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− channel and calcium-activated Cl− channel (TMEM16A) inhibitory activities in T84 and Calu-3 cells, respectively. Four compounds namely dolineon, neodulin, pachyrrhizine, and neotenone inhibited cAMP-induced Cl− secretion across T84 cell monolayers with IC50 values of ~0.81 μM, ~2.42 μM, ~2.87 μM, and ~4.66 μM, respectively. Dolineon having the highest inhibitory activity also inhibited a Ca + activated Cl− channel (TMEM16A) with an IC50 value of ~4.38 μM. The in vitro antidiarrheal activity of dolineon was evaluated on cholera toxin (CT) induced chloride secretion in T84 cells, where it inhibited CT-induced chloride secretion by >70% at 100 μM. Dolineon also inhibited CT-induced fluid secretion by ~70% in an in vivo mouse closed loop model at a dose of 16.9 μg/loop. The cytotoxicity of the extracts and compounds was evaluated on KB, Vero and BHK21 cells, dolineon showed low cytotoxicity of >29.6 μM and 57.30 + 6.77 μM against Vero and BHK21 cells, respectively. Our study revealed that several compounds isolated from N. mitis showed antidiarrheal activity. The most active compound dolineon can potentially serve as a lead compound towards the development of CFTR and TMEM16A inhibitors as future therapeutics for secretory diarrhea.

UOW Authors


  •   Dawurung, Christiana (external author)
  •   Noitem, Rattikarn (external author)
  •   Rattanajak, Roonglawan (external author)
  •   Bunyong, Ratchanu (external author)
  •   Richardson, Christopher
  •   Willis, Anthony (external author)
  •   Kamchonwongpaisan, Sumalee (external author)
  •   Yimnual, Chantapol (external author)
  •   Muanprasat, Chatchai (external author)
  •   Pyne, Stephen

Publication Date


  • 2020

Citation


  • Dawurung, C., Noitem, R., Rattanajak, R., Bunyong, R., Richardson, C., Willis, A., Kamchonwongpaisan, S., Yimnual, C., Muanprasat, C. & Pyne, S. (2020). Isolation of CFTR and TMEM16A inhibitors from Neorautanenia mitis (A. Rich) Verdcourt: Potential lead compounds for treatment of secretory diarrhea. Phytochemistry, 179

Scopus Eid


  • 2-s2.0-85089340983

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2538&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/1504

Volume


  • 179

Place Of Publication


  • United Kingdom

Abstract


  • © 2020 Elsevier Ltd A phytochemical study on the root extracts of Neorautanenia mitis, a Nigerian medicinal plant used in the management of diarrhea, led to the isolation of one new and 19 known natural products. These compounds and crude extracts were evaluated for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− channel and calcium-activated Cl− channel (TMEM16A) inhibitory activities in T84 and Calu-3 cells, respectively. Four compounds namely dolineon, neodulin, pachyrrhizine, and neotenone inhibited cAMP-induced Cl− secretion across T84 cell monolayers with IC50 values of ~0.81 μM, ~2.42 μM, ~2.87 μM, and ~4.66 μM, respectively. Dolineon having the highest inhibitory activity also inhibited a Ca + activated Cl− channel (TMEM16A) with an IC50 value of ~4.38 μM. The in vitro antidiarrheal activity of dolineon was evaluated on cholera toxin (CT) induced chloride secretion in T84 cells, where it inhibited CT-induced chloride secretion by >70% at 100 μM. Dolineon also inhibited CT-induced fluid secretion by ~70% in an in vivo mouse closed loop model at a dose of 16.9 μg/loop. The cytotoxicity of the extracts and compounds was evaluated on KB, Vero and BHK21 cells, dolineon showed low cytotoxicity of >29.6 μM and 57.30 + 6.77 μM against Vero and BHK21 cells, respectively. Our study revealed that several compounds isolated from N. mitis showed antidiarrheal activity. The most active compound dolineon can potentially serve as a lead compound towards the development of CFTR and TMEM16A inhibitors as future therapeutics for secretory diarrhea.

UOW Authors


  •   Dawurung, Christiana (external author)
  •   Noitem, Rattikarn (external author)
  •   Rattanajak, Roonglawan (external author)
  •   Bunyong, Ratchanu (external author)
  •   Richardson, Christopher
  •   Willis, Anthony (external author)
  •   Kamchonwongpaisan, Sumalee (external author)
  •   Yimnual, Chantapol (external author)
  •   Muanprasat, Chatchai (external author)
  •   Pyne, Stephen

Publication Date


  • 2020

Citation


  • Dawurung, C., Noitem, R., Rattanajak, R., Bunyong, R., Richardson, C., Willis, A., Kamchonwongpaisan, S., Yimnual, C., Muanprasat, C. & Pyne, S. (2020). Isolation of CFTR and TMEM16A inhibitors from Neorautanenia mitis (A. Rich) Verdcourt: Potential lead compounds for treatment of secretory diarrhea. Phytochemistry, 179

Scopus Eid


  • 2-s2.0-85089340983

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2538&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/1504

Volume


  • 179

Place Of Publication


  • United Kingdom