On the role of the vinylsulfoxide side chain of dirchromone towards its bioactivities

Abstract

The peculiar vinylsulfoxide side chain of dirchromone plays a pivotal role in the bioactivity of this novel pharmacophore.

Effect of the Chromone Core Substitution of Dirchromone on the Resultant Biological Activities

“…A few exceptions stand out, and 6-hydroxyDC (11) and 6-cyanoDC (15) were less active than DC (1). Among the 6-halides, fluorine (12) and chlorine (13) did not affect cytotoxicity, but bromine (14) sensibly decreased the resultant IC 50 values. The 6-alkoxydes 17d−f reached similar activities to 6-bromoDC (14).…”

“…All compounds were obtained and tested as racemates of the sulfoxide since chirality was shown to have no impact on cytotoxic or antibacterial activities. 13 The effect of the position of substituents was studied by synthesizing DC methylated at positions 3, 5, 6, 7, and 8 (compounds 2−6), as well as four methoxy-substituted DCs (compounds 7−10, of which 8 and 9 were also observed in D. palustris). The importance of the nature of the substituent groups was screened at reference position 6, based on the previous isolation of the methoxy (compound 8) and hydroxy (11) analogues of this series in the plant.…”

“…Overall yields from the starting phenones to the final DCs are summarized in Scheme 1. Finally, 6-hydroxyDC (11) and the corresponding esters (16a−g) were prepared from 6-hydroxy-S-deoxyDC (22), 13 which was esterified using either acyl chlorides and triethylamine or Steglich esterification conditions with the corresponding acids, then proceeding with sulfide to sulfoxide oxidation (Scheme 2).…”

“…This is an interesting property of DCs, because it shows the tolerance to modification of the pharmacophore, previously shown to rely primarily on the vinyl sulfoxide side chain. 13 Addition of lipophilic and/or bulkier substituents to the chromone core, such as bromide, isoamyloxyl, or aryls, potentiated the activity somewhat. Since the DCs did not exhibit much selectivity between normal and cancer cell lines, future design efforts will need to include vectorization strategies.…”

“…12 It was more recently demonstrated that the peculiar vinyl sulfoxide side chain has a high relevance for the aforementioned bioactivities, with the sulfone analogue having addi-tional interest for antimicrobial properties. 13 Results obtained from the original set of eight natural derivatives further suggested that substitution of the chromone moiety also had relevance to modulate the activities: for example, when compared to the parent compound dirchromone (1) (Figure 1), 6-hydroxydirchromone (11) was not cytotoxic against human cell lines but retained some antibacterial activity. This triggered the investigation herein reported of the effects of substituent position, nature, and bulkiness on bioactivity, taking advantage of the straightforward synthetic preparation of dirchromones.…”