Synthesis and biological activity of amino acid derivatives of avarone and its model compound

Abstract

A series of eighteen derivatives of marine sesquiterpene quinone avarone and its model system tert-butylquinone with amino acids has been synthesized by nucleophilic addition of amino acids to the quinones. In vitro cytotoxic activity toward human cancer cell lines (HeLa, A549, Fem-X, K562, MDA-MB-453) and normal MRC-5 cell line was determined. Several compounds showed very strong inhibitory activity with IC50 values less than 10 μM. Avarone derivatives were more active than the corresponding tert-butylquinone derivatives. The results of the cytofluorimetric analysis of cell cycle of HeLa cells showed that apoptosis might be one of possible mechanism of action of these compounds in cancer cells. In order to examine the influence of caspases on cell death, the apoptotic mechanisms induced by the tested compounds were determined using specific caspases 3, 8 and 9 inhibitors. For all compounds antibacterial activities against six strains of Gram-positive and four strains of Gram-negative bacteria were determined, as well as antifungal activity against three fungal species.

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced Form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone

“…In the course of a systematic chemical study of the macroflora and macrofauna of the coastal area of Turkey in theİzmir Bay (Aegean Sea), as a part of our ongoing search for bioactive marine-derived metabolites as leads for drug discovery [15][16][17][18][19][20], we isolated from the sponge Dysidea avara (Schmidt, 1862) the known sesquiterpene quinone avarone (1), along with its reduced form avarol (3, Figure 2) [21][22][23]. A wide range of pharmacological properties have been reported for the redox couple avarone (1) and avarol (3) including anti-tumor [24][25][26], anti-inflammatory [27][28][29], anti-mutagenic [30], anti-bacterial [31,32], anti-viral [33,34], anti-oxidant [23,35], anti-platelet [28], anti-psoriatic [36] and anti-biofouling [37,38] activities. Pharmacological studies on synthetic and semisynthetic derivatives of avarone have been previously reported, too [23,[39][40][41].…”

Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone–Amino Acid Derivatives

“…In order to add new members to this promising chemical series to define the critical structural elements required for potency and selectivity, we are interested in evaluating substances containing biologically relevant nitrogen substituents such as natural α-amino acids. Concerning the design of isoquinolinequinone-α-amino acid derivatives, it was based on the cytotoxic activity of α-amino acid-containing natural occurring 1,4-benzoquinones [14,15,16], 1,4-naphthoquinone [17,18,19], and 9,10-anthraquinone [20].…”

Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential

“…This conclusion is corroborated by the fact that several amino acid derivatives of avarone showed strong antibacterial activity. 21 In general, in order to show a relatively broad activity comparable to amikacin, tert-butylquinone derivatives should have a non-branched medium length alkylamino group or an aralkyl group in position 3′. It is interesting that among the avarone amino acid derivatives, the most active were those with aromatic amino acids, implying that there is an aromatic binding site in a putative target.…”

“…The avarone derivatives were much less active, but in contrast to antibacterial effects, most of them had some activity, although much lower than the amino acid derivatives. 21 The amino acid derivatives of TBQ had weak antimicrobial activity, probably due to their excessive hydrophilicity.…”

“…16 Natural products of marine origin are of particular interest for their diversity of structures and a myriad of activities, together with the vast possibilities for their modifications. [17][18][19] As a continuation of previous work on alkylamino, aralkylamino and amino acid derivatives of avarone and its mimetic tert-butylbenzoquinone (TBQ), 20,21 the synthesis and investigation of the cytotoxic activity of a series of alkylamino and aralkylamino derivatives of avarone and tert-butylbenzoquinone on three cell lines, i.e., non-small cell lung cancer cells, both the sensitive NCI-H460 and multi-drug resistant NCI-H460/R, and healthy human keratinocytes HaCaT are reported herein. Since in a previous work, benzylamino derivatives of tert-butylquinone showed good selectivity for tumour cells, including MDR cells, benzylamino derivatives of avarone were synthesized in the present study.…”