Abstract
Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were stereoselectively synthesised. The acid-catalysed hydrolysis and rearrangement of natural stevioside gave isosteviol, which was transformed to the key intermediate methyl ester. In the next step, Mannich condensation of diterpenoid ketone, paraformaldehyde, and secondary amines resulted in the formation of 1,3-aminoketones with different stereoselectivities. During the Mannich condensation with dibenzylamine, an interesting N-benzyl → N-methyl substituent exchange was observed. Reduction of 1,3-aminoketones produced diastereoisomeric 1,3-aminoalcohols. Alternatively, aminoalcohols were obtained via stereoselective hydroxy-formylation, followed by oxime preparation, reduction, and finally, reductive alkylation of the obtained primary aminoalcohols. An alternative 1,3-aminoalcohol library was prepared by reductive amination of the intermediate 3-hydroxyaldehyde obtained from isosteviol in two-step synthesis. Cytotoxic activity of compounds against human tumour cell lines (A2780, SiHa, HeLa, MCF-7 and MDA-MB-231) was investigated. In our preliminary study, the 1,3-aminoalcohol function and N-benzyl substitution seemed to be essential for the reliable antiproliferative activity. To extend their application, a diterpenoid condensed with 2-phenylimino-1,3-thiazine and -1,3-oxazine was also attempted to prepare, but only formation of thioether intermediate was observed.
Highlights
Terpenoids, known as isoprenoids, are the most numerous and structurally diverse group of natural products present in most plants [1]
We report the preparation of a new library of isosteviolbased chiral bifunctional synthons, such as β-aminoketones, 1,3-aminoalcohols, and 1,3heterocycles fused with ent-beyerane, starting from commercially available natural stevioside
A series of novel isosteviol derivatives containing 1,3-aminoalcohol and thiourea moieties have been synthesised with moderated to good yields, and their cytotoxic activities against five human cancer cell lines (HeLa, Siha, MCF7, MDA-MB-231, A2780)
Summary
Terpenoids, known as isoprenoids, are the most numerous and structurally diverse group of natural products present in most plants [1]. The diterpenoid stevioside with a complex ent-kaurane skeleton and three glucose moieties has been the focus of attention in recent decades [3,4]. Stevioside is extracted from the plant Stevia rebaudiana, which is a perennial herbal shrub of the Asteraceae family that originated from Brazil and Paraguay in South America, while cultivated for its sweet leaves [5]. It is applied in food chemistry as a commercial sweetener considered to be a non-caloric sugar substitute. Stevioside and steviol, its aglycon, have attracted scientific attention because of their broad spectrum of biological activities, including antihyperglycemic, [6] antihypertensive, [7,8] antitumour, [9,10] and immunomodulatory actions [11] beside several other biological activities [12,13]
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