Pharmaceutical Research

, 35:175 | Cite as

Effect of Tumor Relevant Acidic Environment in the Interaction of a N-hydroxyindole-2-Carboxylic Derivative with the Phospholipid Bilayer

  • Daniela Monti
  • Silvia Tampucci
  • Erica Zucchetti
  • Carlotta Granchi
  • Filippo Minutolo
  • Anna Maria PirasEmail author
Research Paper



The inhibitors of the human isoform 5 of lactate dehydrogenase (hLDH5) have attracted growing interest as efficient anti-cancer agents. In the present paper, the interactions between an efficient hLDH5 inhibitor (N-hydroxyindole-2-carboxylic derivative) and lipid bilayers based on dipalmitoylphosphatidylcholine (DPPC) were investigated. Additionally, since interstitial acidification plays a key role in tumor pathogenesis and tumor drug therapy, the effect of acidic pH was assessed and correlated to DPPC/drug interaction.


Four different techniques were used: differential scanning calorimetry, dynamic light scattering, UV-VIS second derivative spectrometry and attenuated total reflection Fourier transformed infrared spectroscopy.


All techniques concur in highlighting a structural change of lipid assembly, susceptible both to pH change and to the presence of the antitumor compound. Lipid vesicles appeared more compact at the lower pH, since the thermal pre-transition from the lamellar gel phase to the ripple gel phase was absent at pH 7.4 and the infrared analysis revealed a stronger acyl chain packing as well as a different hydration degree. Drug interaction was mainly detected in the lipid region including the ester linkages and the first portion of the acyl chains. Furthermore, a lower drug partitioning was recorded at pH 6.6.


The investigated antitumor agent possesses a stable negative charge at the investigated pH values, thus the lower interaction at the acidic pH is mainly ascribable to an environmental effect on lipid assembly. Therefore, drug efficacy under tumor acid conditions may be hampered by the observed lipid membrane constraints, and suggest for the development of suitable prodrugs.


Dipalmitoylphosphatidylcholine (DPPC) hLDH5 inhibitor N-hydroxyindole derivatives tumor acidic pH 



Attenuated total reflection Fourier transformed infrared spectroscopy




Dynamic light scattering




Differential scanning calorimetry


1-Hydroxy-6-phenyl-4-(trifluoromethyl)-1Hindol-2-carboxylic acid


Human isoform 5 of lactate dehydrogenase




Acknowledgments and Disclosures

The research project was supported by Progetti di ricerca di Ateneo PRA 2017 of the University of Pisa.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacyUniversity of PisaPisaItaly

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