Synthesis of New Chiral Derivatives of Xanthones with Enantioselective Effect on Tumor Cell Growth and DNA Crosslinking

Abstract

A new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthesized for antitumor evaluation. Two carboxyxanthones (1 and 2) were used as chemical substrates and coupled with selected chiral building blocks (43–62), achieving yields and enantiomeric excess (ee) values higher than 92 and 99 %, respectively. Carboxyxanthones 1 and 2 were synthesized, by a multi‐step synthetic pathway via diaryl ether intermediate (Ullman reaction), being compound 2 described here for the first time. The evaluation of the growth inhibitory activity allowed to find active chiral compounds for all the tested cells lines, and to establish structure‐activity relationship (SAR) considerations. In some cases, the growth inhibitory effects demonstrated to be dependent on the stereochemistry of the compounds. Interestingly, the most active compound (12) and its enantiomer (11) demonstrated high enantioselectivity for MCF‐7 breast adenocarcinoma cell line. In addition, in vitro DNA crosslinking ability was assessed and the results correlated with in vitro cytotoxicity.

From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones

“…The inhibitory activity of the racemates C-E as well as of the corresponding enantiomers on in vitro growth of the human breast adenocarcinoma cell line MCF-7 was evaluated and compared. The most evident enantioselectivity was found between the racemate of trans -kielcorin D ( 62 ) (inactive) and the active enantiomers (+)- 62 and (−)- 62 ( Figure 16 ) [ 68 , 134 , 135 , 136 ].…”

“…Considering that carboxyxanthone derivatives are appropriate chemical substrates to perform molecular modifications to obtain diverse derivatives and analogues [ 138 ], we selected different compounds, comprising one or more carboxylic groups, to perform the referred syntheses [ 68 , 135 , 136 , 137 ]. Both enantiomers of a variety of amino alcohols, amines, and amino esters were chosen as chiral building blocks, containing a primary amine as reactive group for amide formation ( Figure 17 ).…”

“…TBTU has been broadly used as an effective reagent for the synthesis of varied classes of compounds [ 139 ] however, our group reported for the first time the use of this coupled reagent to synthetize CDXs [ 137 ]. All coupling reactions were carried out at room temperature, showing short reactions times (ranging from 20 min to 6 h) and excellent yields (ranging from 92% to 99%) [ 135 , 136 , 137 ]. The synthetic methodology proved to be very efficient, with broad-scope applicability, and simple operationally.…”

“…Thirty-one enantiomeric pairs of the synthesized CDXs were evaluated for the in vitro growth inhibitory activity in three human tumor cell lines, A375-C5 (melanoma), MCF-7 (breast adenocarcinoma), and NCI-H460 (non-small cell lung cancer) [ 135 , 136 ]. The obtained results allowed to find active chiral compounds for all the tested cells lines, with some showing cell-type selectivity, and to draw SAR considerations.…”

“…Another feature that has a decisive role on the growth inhibitory effect was the configuration of the stereogenic center(s). The most active CDXs in all human tumor cell lines were ( R , S )- 65 [ 135 ] and ( R )- 69 [ 136 ] ( Figure 16 ). Both enantiomers of CDX 63 also revealed promising results [ 136 ] ( Figure 16 ).…”