Abstract
Marine-originated spirocyclic bromotyrosines are considered as promising scaffolds for new anticancer drugs. In a continuation of our research to develop potent and more selective anticancer compounds, we synthesized a library of 32 spirocyclic clavatadine analogs by replacing the agmatine, i.e., 4-(aminobutyl)guanidine, side chain with different substituents. These compounds were tested for cytotoxicity against skin cancer using the human melanoma cell line (A-375) and normal human skin fibroblast cell line (Hs27). The highest cytotoxicity against the A-375 cell line was observed for dichloro compound 18 (CC50 0.4 ± 0.3 µM, selectivity index (SI) 2). The variation of selectivity ranged from SI 0.4 to reach 2.4 for the pyridin-2-yl derivative 29 and hydrazide analog of 2-picoline 37. The structure–activity relationships of the compounds in respect to cytotoxicity and selectivity toward cancer cell lines are discussed.
Highlights
Orazio Taglialatela-ScafatiNatural products have a long history of use in the treatment of various diseases, including cancer [1]
The of the of spirocyclic bromotyrosine scaffold started with esterification ofC 11, and Thesynthesis cytotoxicities the11–42 synthetic
The ester 7 was oxidized with sodium tungstate and H2O2 to give the were tested against a melanoma cell line (A-375)
Summary
Orazio Taglialatela-ScafatiNatural products have a long history of use in the treatment of various diseases, including cancer [1]. Many marine-derived bioactive terpenes, alkaloids, macrolides, and other compounds isolated from aquatic fungi, cyanobacteria, algae, sponges, and tunicates have been found to exhibit anticancer activities [2,3]. Nine of these drugs are registered for the treatment of different cancer types [4,5]. Bromotyrosine alkaloids have acquired special importance in medicinal chemistry since the vast majority of these secondary metabolites possess potential anticancer [6], antimicrobial, antiviral, and antifungal activities [7,8]. Quinn and co-workers identified two new spirocyclic bromotyrosine compounds, clavatadine C 1 and clavatadine D 2 (Figure 1). Both were isolated as trifluoroacetic acid (TFA) salts from the marine sponge Suberea clavata and their anticoagulative properties were described. Marine bromotyrosines with an isoxazoline moiety attached to the spiro center have exhibited anticancer properties [11,12]
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