Geldanamycin-inspired compounds induce direct trans-differentiation of human mesenchymal stem cells to neurons

Srinivas Jogula, Anand Ram Soorneedi, Jagan Gaddam, Srinivas Chamakuri, Girdhar Singh Deora, Ranjith Kumar Indarapu, Murali Krishna Ramgopal, Subhadra Dravida, Prabhat Arya

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1 Citation (Scopus)

Abstract

Inspired from geldanamycin, the synthesis of a new series of 20-membered macrocyclic compounds is developed. The key features in our design are (i) retention of the fragment having the precise chiral functional groups of geldanamycin at C10, C11, C12 and C14, and (ii) replacement of an olefin moiety with the ester group, and the quinoid sub-structure with the triazole ring. The southern fragment needed for the macrocyclic ring formation was obtained from Evans' syn aldol as the key reaction and with the use of D-mannitol as the cheap source of a chiral starting material. For the synthesis of the northern fragment, we utilized L-ascorbic acid, which provided the desired chiral functional groups at C6 and C7. Further, the chain extension completed the synthesis of the northern fragment. In our approach, the crucial 20 membered macrocyclic ring was formed employing the click chemistry. When tested for their ability to directly trans-differentiate human mesenchymal stem cells to neurons, two novel compounds (20a and 7) from this series were identified and this was further validated by the presence of specific neuronal biomarkers (i.e. nestin, agrin and RTN4).

Original languageEnglish
Pages (from-to)110-116
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Volume135
DOIs
Publication statusPublished - 2017
Externally publishedYes

Keywords

  • Chemical approaches to trans-differentiation
  • Geldanamycin
  • Geldanamycin-inspired compounds
  • Human mesenchymal stem cells
  • Natural product-inspired compounds
  • Stem cells to neurons
  • Trans-differentiation

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