Synthesis of amide isosteres of schweinfurthin-based stilbenes

Abstract

The schweinfurthins are plant-derived stilbenes with an intriguing profile of anti-cancer activity. To obtain analogues of the schweinfurthins that might preserve the biological activity but have greater water solubility, a formal replacement of the central olefin with an amide has been explored. Two pairs of amides have been prepared, each containing the same hexahydroxanthene “left half” joined through an amide linkage to two different “right halves.” In each series, the amide has been inserted in both possible orientations, placing the carbonyl group on the tricyclic ABC ring system and the amine on the D-ring, or placing the amine on the hexahydroxanthene and the carbonyl group on the D-ring. The four new schweinfurthin analogues have been tested in the NCI 60 cell line screen, and in both cases the more active isomer carried the carbonyl group on the C-ring.

Schweinfurthins: Lipid Modulators with Promising Anticancer Activity

“…These studies also showed that reduction to the alkane linker reduced activity, though not as much as isomerization did, suggesting that the ethyl linkage could still adopt a somewhat favorable transoid orientation. Early studies suggested a tentative connection between cLogP values and cytotoxicity, though the replacement of the olefin with an amide bond altered cLogP, but not cytotoxicity, significantly (Stockdale et al, ; Ulrich et al, ). In this study, the olefin was replaced with an amide bond in both orientations (amine on the C‐ring vs amine on the D‐ring) in an effort to increase solubility (Stockdale et al, ).…”

“…Early studies suggested a tentative connection between cLogP values and cytotoxicity, though the replacement of the olefin with an amide bond altered cLogP, but not cytotoxicity, significantly (Stockdale et al, ; Ulrich et al, ). In this study, the olefin was replaced with an amide bond in both orientations (amine on the C‐ring vs amine on the D‐ring) in an effort to increase solubility (Stockdale et al, ). The calculated cLogP values were lower, indicating the potential for more favorable drug‐like properties (e.g.…”

Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres

“…Amide isosteres of resveratrol have shown activity similar to the parent compound [31]. The amide linkage should allow to maintain the transoid architecture of the trans-stilbene, conferring however improved solubility and increased polarity [32,33] as well as differences in electronic perturbations [32,33]. Therefore, analogue 15 was synthesized (Scheme 2).…”

Styryl Group, a Friend or Foe in Medicinal Chemistry

“…The cis-and trans-isomers of combretastatins display varying effects on tubulin polymerization. The active form of the combretastatin A4 exists as a cisisomer 79 as it mimics the 3D conformation of colchicine (114) and thus, it perfectly occupies the colchicine-binding site of tubulin (Figure 21b).…”

“…There is no difference in Log P and polar surface area among two amide isosteres, 167 and 168 . Thus, the threefold activity difference in them could be attributed to the differences in 3D‐conformation and molecular interactions at the target active site [114] . Distamycin is a pyrrole‐amidine class of oligopeptide antibiotic produced by Streptomyces distallicus that binds to the DNA minor groove.…”