Peroxyhemiacetal MonoKeto-​Aldehyde (MKA) is a DiHydroArtemisinin (DHA) deriv., still endowed with significant (on a ng-​scale) in vitro antimalarial activity and neurotoxicity lower than that displayed by its precursor. Through literature it is known that MKA may be formed under essentially physiol. conditions (org.-​aq. environments buffered at pH 7.4) or prepd. by acid decompn. of DHA in water to afford yields that, however, do not reach 50​%. A more convenient procedure of prepn. is here reported at room temp. Owing to its hemiacetal nature MKA was expected to occur in soln. as a mixt. of α and β epimers. In the present study this, in fact, has been demonstrated through dynamic chromatog. measurements, which allowed to highlight that for MKA the α→β equilibration is about 3 times slower than for DHA. In consideration of the propensity of MKA to originate by DHA in mild both acid and base conditions, its formation appears possible during the stages of prodn. and storage of its parent drug and also widely expected in physiol. environment. Thus, the improvement of knowledge about this product of DHA degrdn. could have useful impact in the rational development of new methods for the anal. of purity of DHA in its pharmaceutical formulations, as well as in taking into account the biol. activity expressible in vivo by the mixt. of α and β epimers of MKA, whose equil. compn. is a function of the met specific biol. environment. In this context, in our study we elucidated the stereo-​structure of the epimers of MKA through NMR measurements and performed a comprehensive thermodn. investigation of the process that governs the related interconversion through Linear Solvation Energy Relationships (LSER) approach. A convincing rationalization of the whole findings has then been achieved through support from mol. modeling calcns.

Thermodynamic and Kinetic Investigation of Monoketo-​Aldehyde-​Peroxyhemiacetal-​(MKA)​, a Stereolabile Degradation Product of Dihydroartemisinin / Kotoni, Dorina; M., Piras; W., Cabri; F., Giorgi; A., Mazzanti; Pierini, Marco; M., Quaglia; Villani, Claudio; Gasparrini, Francesco. - In: RSC ADVANCES. - ISSN 2046-2069. - STAMPA. - 4:(2014), pp. 32847-32857. [10.1039/C4RA00879K]

Thermodynamic and Kinetic Investigation of Monoketo-​Aldehyde-​Peroxyhemiacetal-​(MKA)​, a Stereolabile Degradation Product of Dihydroartemisinin.

KOTONI, DORINA;PIERINI, MARCO;VILLANI, Claudio;GASPARRINI, Francesco
2014

Abstract

Peroxyhemiacetal MonoKeto-​Aldehyde (MKA) is a DiHydroArtemisinin (DHA) deriv., still endowed with significant (on a ng-​scale) in vitro antimalarial activity and neurotoxicity lower than that displayed by its precursor. Through literature it is known that MKA may be formed under essentially physiol. conditions (org.-​aq. environments buffered at pH 7.4) or prepd. by acid decompn. of DHA in water to afford yields that, however, do not reach 50​%. A more convenient procedure of prepn. is here reported at room temp. Owing to its hemiacetal nature MKA was expected to occur in soln. as a mixt. of α and β epimers. In the present study this, in fact, has been demonstrated through dynamic chromatog. measurements, which allowed to highlight that for MKA the α→β equilibration is about 3 times slower than for DHA. In consideration of the propensity of MKA to originate by DHA in mild both acid and base conditions, its formation appears possible during the stages of prodn. and storage of its parent drug and also widely expected in physiol. environment. Thus, the improvement of knowledge about this product of DHA degrdn. could have useful impact in the rational development of new methods for the anal. of purity of DHA in its pharmaceutical formulations, as well as in taking into account the biol. activity expressible in vivo by the mixt. of α and β epimers of MKA, whose equil. compn. is a function of the met specific biol. environment. In this context, in our study we elucidated the stereo-​structure of the epimers of MKA through NMR measurements and performed a comprehensive thermodn. investigation of the process that governs the related interconversion through Linear Solvation Energy Relationships (LSER) approach. A convincing rationalization of the whole findings has then been achieved through support from mol. modeling calcns.
2014
01 Pubblicazione su rivista::01a Articolo in rivista
Thermodynamic and Kinetic Investigation of Monoketo-​Aldehyde-​Peroxyhemiacetal-​(MKA)​, a Stereolabile Degradation Product of Dihydroartemisinin / Kotoni, Dorina; M., Piras; W., Cabri; F., Giorgi; A., Mazzanti; Pierini, Marco; M., Quaglia; Villani, Claudio; Gasparrini, Francesco. - In: RSC ADVANCES. - ISSN 2046-2069. - STAMPA. - 4:(2014), pp. 32847-32857. [10.1039/C4RA00879K]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/585787
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