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Selective protection of protoescigenin as the key step in synthesis of escin analogs

Mariusz M. Gruza 1Kamil Jatczak 1Katarzyna E. Filip 1Piotr Cmoch 1,2Grzegorz Grynkiewicz 1

1. Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland
2. Institute of Organic chemistry of the Polish Academy of Sciences (ICHOPAS), Kasprzaka 44/52, Warsaw 01-224, Poland


Escin, an active pharmaceutical ingredient of innumerable pharmaceutical preparations, consists of a complex mixture of some tens of triterpenoid saponins with similar structures, practically inseparable and rather poorly characterized. Herbal material, which is isolated from seed of the horse chestnut (Aesculum hippocastanum L.) has good clinical opinion as a remedy for chronic venous insufficiency and vain varicose. Yet, from the scientific point of view, the escin mixture is not compatible with modern principle of evidence based medicine, postulating  API with strictly defined physical, chemical and pharmacological properties.

Our study of escin has been focused on a switch from multicomponent mixture of natural saponins to properly characterized, high purity individual chemical entities, with preserved pentacyclic triterpene scaffold. It has been already demonstrated [1] that such a change is feasible, based on technical scale preparation of protoescigenin (PES) – the main aglycone (genin) of the escin complex. Following application of semi-synthesis can have multidirectional design, but critically depends on reactivity and selectivity of the six  hydroxyl groups present in the olean-12-en structure, which have practically not been explored before. Thus, systematic and critical survey of PES derivatization, with application of acylating, alkylating, and silylating reagents have been carried out – the most desirable feature being the ability to obtain a derivative in a state of reasonable chemical purity, without resort to chromatographic methods of isolation. In our hands, only ketalization has met such criteria, which in turn severely limited a scope of follow up derivatization, among which chemical glycosylation has been considered a priority. In search for a compromise between chemical feasibility and functional needs, “click chemistry” dipolar cycloaddition based on azide - alkyne ligation has been selected and evaluated as suitable synthetic tool. Necessary propargyl ethers of PES were obtained by standard method and according to expectation their tagging with variety of azides allowed for introduction of desired functionality, e.g. sugar conjugation or solubility enhancing moiety.


Support from European and Regional Funds under project POIG.0101.02-14-072/09-00 grant  „Search of innovative endothelial drug in a group of new escin derivatives” Project  Leader: prof. dr hab. Katarzyna Koziak, Department of General and Nutritional Biochemistry, Warsaw Medical University, Żwirki i Wigury 61, Warszawa 02-091, Poland;


[1]    Gruza, M.; Jatczak, K.; Zagrodzki, B.; Łaszcz, M.; Koziak, K.; Malińska, M.; Cmoch, P.; Giller, T.; Zegrocka-Stendel, O.; Woźniak, K.; Grynkiewicz, G. Molecules 2013, 18, 4389–4402; doi:10.3390/molecules18044389


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Related papers

Presentation: Poster at IX Multidyscyplinarna Konferencja Nauki o Leku, by Mariusz M. Gruza
See On-line Journal of IX Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2014-03-13 10:35
Revised:   2014-05-02 10:26