Design, Synthesis And Biological Evaluation Of Cis-4-hydroxy-L- Proline Derivatives Nerve Growth Promoting Agent

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s syndrome, Huntington’s disease, Frontotemporal dementia, Amyotrophic lateral sclerosis, and occur mainly in the elderly population. They are degenerative neurological disease, and are caused by a class of neurodegenerative diseases. Currently aging has become more evident, the incidence of these diseases also will increase. They are difficult to heal, so they bring great harm. Endogenous nerve growth factor, although has a significant effect, but as biological macromolecules it is difficult to apply in clinical practice. Therefore, the search of small molecules within easy through the blood-brain barrier, administered orally, good bioavailability as nerve alternatives for the treatment of neurodegenerative diseases is important.Immunosuppressant FK506 has been identified to neuroprotection and nerve regeneration, make people aware of the effects of FK506-binding protein(FKBPs) may be a new target for treatment of neurodegenerative diseases. The structure of FK506 is divided into two sections, namely, the combined area and the effect area, its combined region and FKBP12 active site combine to form F506-FKBP12 complexes. The complexes combine to calcineurin through the effect area of FK506 and binding, inhibiting calcineurin-induced t-cell nucleus to phosphorylation, then it will hinder the transfer of t-cell nucleus to nucleus, block the synthesis of interleukin 2 and get the function of immunosuppression. The neuroprotection and nerve regeneration function of FK506 depends on combination of FK506-binding domain and FKBP12. Thus, it begins the research of the design and synthesis of non-immunosuppressive but neuroprotective and nerve growth based on FK506-binding domain structure.According to the structure of FKBP12,FK506-binding domain, as well as small molecule ligand structure of GPI-1046, data analysis by using SYBYL software for computer-aided drug design, we find that there is a space between the FK506 and GPI-1046 by combination with FKBP12, and water molecules can fit the size of the space. This design introduced on the 4th position in the GPI-1046 by a hydroxyl, it can fill the space. When due to the introduction of CIS-hydroxy, it may form hydrogen bonds with 26 th tyrosine of FKBP12, strengthening the role of small molecule ligand and protein, so we consider the introduction of CIS-hydroxy.According to this idea, from simple raw materials based on the CIS-hydroxy-Ll-Proline, thtough eight steps, and 17 target compounds are synthesized. These compounds are confirmed MS, 1H-NMR. We use PC12 cells for vitro models, in the NGF conditions, the target compounds effect on PC12 cells, PC12 cells differentiation as indicators to measure whether the target compounds can promote the differentiation of PC12 cells induced by NGF and screening compounds that promote nerve regeneration. Among them, 15 compounds being tested are higher than the NGF control group, it states that this series of compounds that can promote the differentiation of PC12 cells induced by NGF, can be a value for further study.