Abstract
Dried leaves of Catharanthus roseus were extracted with aqueous acidic 0.1 M solution of HCl. Alkaloid-embonate complexes were obtained as precipitates by treating the extract with an alkaline (NaOH) solution of embonic acid (4,4-methylene-bis-3-hydroxynaphtalenecarboxylic acid). The precipitate mainly consisted of catharanthine and vindoline embonates and it was directly used as the starting material for a semi-synthesis of the anti-cancer bisindole alkaloid vinblastine. The coupling reaction involved oxidation of catharanthine in aqueous acidic medium by singlet oxygen ((1)O2), continuously produced in situ by the reaction between H2O2 with NaClO. An excess of NaBH4 was used for the reduction step. Analysis of the reaction mixture indicated a maximum yield of 20% for vinblastine at pH 8.3, based on the initial amount of catharanthine concentration. Direct-injection electrospray ionization mass spectrometry in positive ion mode was used for the identification of vinblastine. The mass spectra of vinblastine were dominated by the corresponding protonated molecular ion [M+H]+ at m/z 811 and the characteristic fragment ions matched with those of the standard compound.
Highlights
The precipitate mainly consisted of catharanthine and vindoline embonates and it was directly used as the starting material for a semisynthesis of the anti-cancer bisindole alkaloid vinblastine
The traditional solid-liquid extraction procedure for Catharanthus alkaloids from an aqueous acidic medium is based on their general basic properties
Water insoluble embonic acid complexes of catharanthine and vindoline were prepared by adding an aqueous alkaline solution of embonic acid to the aqueous acidic solution of the plant extract containing the alkaloids as their soluble hydrochloride salts
Summary
Low "dimeric" alkaloid contents in the plant have encouraged intense research for alternative production methods involving cell cultures [2,3], metabolic engineering [4], semi-synthesis [5,6] or even total chemical synthesis [7]. Various semi-synthetic procedures have been developed for these alkaloids on the basis of chemical [5,6] or enzymatic [8] coupling of commercially available catharanthine and vindoline (Figure 1, A, B). In this work compounds from the reaction mixture were analyzed and identified using HPLC-UV and the identification was confirmed by direct-injection ESI-MS/MS in positive ion mode. Embonic acid (4,4’-methylene-bis-3-hydroxynaphtalenecarboxylic aci, Figure 1, C) and iii) to carry out the synthesis of vinblastine and related dimeric alkaloids by directly using the above precipitate as starting material
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