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

• Published in: European journal of medicinal chemistry Vol. 135; pp. 110 - 116
• Main Authors: Jogula, Srinivas, Soorneedi, Anand Ram, Gaddam, Jagan, Chamakuri, Srinivas, Deora, Girdhar Singh, Indarapu, Ranjith Kumar, Ramgopal, Murali Krishna, Dravida, Subhadra, Arya, Prabhat
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 28.07.2017; Elsevier
• Subjects: Benzoquinones - chemical synthesis; Benzoquinones - chemistry; Benzoquinones - pharmacology; Cell Differentiation - drug effects; Chemical approaches to trans-differentiation; Chemistry, Medicinal; Dose-Response Relationship, Drug; Geldanamycin; Geldanamycin-inspired compounds; Human mesenchymal stem cells; Humans; Lactams, Macrocyclic - chemical synthesis; Lactams, Macrocyclic - chemistry; Lactams, Macrocyclic - pharmacology; Life Sciences & Biomedicine; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Molecular Structure; Natural product-inspired compounds; Neurons - cytology; Neurons - drug effects; Pharmacology & Pharmacy; Science & Technology; Stem cells to neurons; Structure-Activity Relationship; Trans-differentiation; Geldanamycin-inspired compounds; Stem cells to neurons; Trans-differentiation; Natural product-inspired compounds; Human mesenchymal stem cells; Geldanamycin; Chemical approaches to trans-differentiation; MOUSE FIBROBLASTS; COMPLEX; DESIGN; SMALL-MOLECULE; RADICICOL; PROTEIN 90 HSP90; CHAPERONE; PANCREATIC BETA-CELLS; INHIBITORS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.03.082

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). [Display omitted]