Synthesis and cytotoxic activity of α-santonin amino-derivatives

Abstract

Previously unknown amino-derivatives of the natural sesquiterpene lactone α-santonin were synthesized. The activity of the products against several human tumor-cell lines was studied.Natural sesquiterpene lactones exhibit various types of biological activity including antitumor activity [1]. A study of structure-activity relationships has found that high cytotoxicity correlates with the presence of an exocyclic double bond in the lactone ring [2]. Furthermore, the presence of an activated double bond allows modification (by a Michael reaction), introduction of new pharmacophores, and production of water-soluble and transportable forms [3].Compounds containing in a lactone ring not a methylene group but a methyl are found among the large variety of natural sesquiterpene γ-lactones isolated from plants of the family Asteraceae. For example, austricin (1) [4] was isolated from Artemisia leucodes Schrenk, A. austriaca Jacg.; arborescin (2) [5], from A. arborescens L.; and balchanolide (3) [6], from Achillea millefolium L. and A. balchanorum H. Krasch, etc.These and other sesquiterpene lactones with a methyl in the lactone ring are found in plants in large quantities and can be considered promising synthons for modification in order to introduce a new reactive center such as an activated exocyclic double bond that reacts readily with nuclophiles. These transformations could produce new derivatives of natural sesquiterpene lactones containing pharmacophores and their water-soluble or transportable forms.Our goal was to use α-santonin (4), which is isolated from certain Artemisia species (Asteracea), as an example to demonstrate the ability to introduce an active methylene into the lactone ring, to use the resulting lactone as a synthon for synthesis of previously unknown amino-derivatives of lactones, and to study their cytotoxic activity.Chemical and biochemical transformations of α-santonin and its pharmacological properties have been studied already for over 100 years. It has been used previously as an antiparasite preparation [7]. Other types of activity have recently been found for it, for example, antipyretic, anti-inflammatory, and fungicidal [8,9]. Santonin presents several reactive centers and is a convenient starting material for further chemical modification. Various transformations involving the dienone ring have been reported [10][11][12][13]. Methods for opening the lactone ring using various reagents are known [1,14,15].

Natural sesquiterpenoids

“…272 7a-Hydroxyfrullanolide 293 has been biotransformed by several fungi with the aim of preparing metabolites with antibacterial activity. 273 The synthesis and cytotoxic activity of a-santonin amino-derivatives have been described, 274 whilst the epoxidation of ludartin and tourneforin has been studied. 275 A total synthesis of racemic axamide-1 and axisonitrile-1 has been reported.…”

Natural Sesquiterpene Lactones as Renewable Chemical Materials for New Medicinal Products

“…Previously unknown amine derivatives (16-17) of α-santonin (1) were synthesized and studied for their activity against tumor human cell lines [19].…”

“…[24] conducted the reactions of artemisinin (18) with ethanolamine. Authors isolated and identified corresponding lactam (19) from the reaction mixture. Reaction of artemisinin (18) with ethylene diamine led to a dimer (20).…”

Fluorinated Amino-Derivatives of the Sesquiterpene Lactone, Parthenolide, as 19F NMR Probes in Deuterium-Free Environments

“…To address this shortcoming, amines have been added to the α-methylene-γ-lactone substructure as an efficient way to enhance the water solubility of the parent molecules and to retain their biological activity. Amino-adducts have been prepared from the sesquiterpene lactones, alantolactone, 3 costunolide, 4 parthenolide ( 1 ), 5–7 α-santonin, 8 helenalin, 9 and ambrosin (Figure 1). 10 A key amino-adduct of parthenolide (i.e.…”

“…To address this shortcoming, amines have been added to the α-methylene-γ-lactone substructure as an efficient way to enhance the water solubility of the parent molecules and to retain their biological activity. Amino-adducts have been prepared from the sesquiterpene lactones, alantolactone, costunolide, parthenolide ( 1 ), − α-santonin, helenalin, and ambrosin (Figure ) . A key amino-adduct of parthenolide (i.e., DMAPT or LC-1) has advanced into clinical studies in humans − despite a long-standing bias in medicinal chemistry against using molecules with a potential covalent mechanism of action in clinical trials .…”