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UNIVERSITA’ DEGLI STUDI DI MILANO PhD IN CHEMICAL SCIENCES XXII CYCLE

UNIVERSITA’ DEGLI STUDI DI MILANO PhD IN CHEMICAL SCIENCES XXII CYCLE. Histidine and deuterium labelled histidine by asymmetric catalytic reduction. Daniele Sergio ZERLA Matr. R07227. Tutor: Chiar.mo Prof. E.CESAROTTI. H 2. Χ. Cat* Rh(I). Histidine. Carnosine. WHY HISTIDINE?.

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UNIVERSITA’ DEGLI STUDI DI MILANO PhD IN CHEMICAL SCIENCES XXII CYCLE

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  1. UNIVERSITA’ DEGLI STUDI DI MILANO PhD IN CHEMICAL SCIENCES XXII CYCLE Histidine and deuterium labelled histidine by asymmetric catalytic reduction Daniele Sergio ZERLA Matr. R07227 Tutor: Chiar.mo Prof. E.CESAROTTI

  2. H2 Χ Cat* Rh(I)

  3. Histidine Carnosine WHY HISTIDINE? D- e L- Carnosine: used for the preparation of a medicament or diet supplement for the treatment or prevention of disorders induced by oxidative stress which are characterized by the formation of cytotoxic carbonyl compounds in the body. These disorders are neurodegenerative ones like Alzhheimer’s, Parkinson’s and ALS, diabetes and the complications thereof, atherosclerosis, age-associated tissue degeneration, sarcopenia, nephropathy, vascular dysfunction, hypertriglyceridemia, hypercholesterolemia, hypertension in metabolic syndromes. L- Carnosine: endogenous dipeptide (b-alanyl-L-Histidine) presents in the human muscles and nerve tissue. It has the ability to react with toxic aldehydes deriving from metabolic pathway of oxidative degradation of endogenous compounds and so it has a protective and detoxifying effect on the toxic metabolites.

  4. Only when ippuric acid is used we have the azlactone and than the corresponding dehydro amino acid If the pharmacological results are encuraging the next target is synthesize and deuterate some derivates of dehydro-histidine characterized by substituted imidazolyl ring, in order to study the pharmacological property of the corresponding carnosine derivatives.

  5. [PP(Rh)COD]+ClO4- MeOH H2 HBF4

  6. [PP(Rh)COD]+ClO4- + Solv. HBF4 D2

  7. [PP(Rh)COD]+ClO4- + Solv. HBF4 D2

  8. The presence of monodeuterated product is due to the competition between reductive elimination and protonation/hydrolysis on the σ-deutero-Rh-alkyl-intermediate.

  9. conclusion We found the best condition for hydrogenation and deuteration of dehydro-histidine, however we can’t synthesize the dehydro-carnosine to go straightforward to carnosine with asymmetric reduction; we has synthesized labelled D-histidine as precursor of non natural carnosine using for “in vivo” pharmacological studies. work in progress Study other strong acid like HClO4, CH3SO3H, CF3SO3H(D) as additives and determining their activity on yield, e.e. and percentage of monodeuterated product. Synthesize other derivates of dehydro-histidine characterized by substituted imidazolyl ring.

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