Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-ones as curcumin-based anticancer agents

Abstract

Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 μM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction.

Design, synthesis, and biological evaluation of 1,9-diheteroarylnona-1,3,6,8-tetraen-5-ones as a new class of anti-prostate cancer agents

“…5 and 6 ). 20 However, the current study indicates that these two groups of heteroaromatic rings can only bestow moderate antiproliferative potency to 1,9-diarylnona-1,3,6,8-tetraen-5-ones (e.g. 82 and 69 ).…”

“…82 and 69 ). As illustrated in Table 3, the optimal 1,5-diheteroarylpenta-1,4-dien-3-one ( 3 ) 19 has much greater anti-proliferative potency than 5 and 78 , the optimal mimics from 1,7-diheteroarylhepta-1,4,6-trien-3-ones 20 and 1,9-diarylnona-1,3,6,8-tetraen-5-ones. This indicates that the length of the linker exhibits important impact on anti-proliferative potency of these curcumin mimics and that the scaffold with 5-carbon linker is the most promising one.…”

“…The 1 H NMR data for the sixteen known ( E )-3-aryl-2-propenals ( 33 , 34 , 36 , 37 , 39-46 , 48 , 49 , 56 , 57 ) are in consistent with those reported in the literature. 20 The yields and 1 H NMR spectral data for the other nine intermediates are listed below.…”

Structure-activity relationship studies of 1,7-diheteroarylhepta-1,4,6-trien-3-ones with two different terminal rings in prostate epithelial cell models

“…Chemical manipulations on curcumin have been established as a meaningful approach to the development of curcumin-based anti-prostate cancer agents with more drug-like properties [5]. 1,5-Diheteroarylpenta-1,4-dienones [6,7], 1,7-diheteroarylhepta-1,4,6-trienones [8], and 1,9-diheteroarylnona-1,4,6,8-tetraenones [9] have been identified by us as potential scaffolds for developing curcumin-based anti-prostate cancer agents because of their apparently improved potency as compared with curcumin. Among them, the 1,4,6-trienone motif was envisioned and illustrated as a good bioisostere of the keto-enol central spacer in curcumin due to the indistinguishable shape and size [8].…”

“…1,5-Diheteroarylpenta-1,4-dienones [6,7], 1,7-diheteroarylhepta-1,4,6-trienones [8], and 1,9-diheteroarylnona-1,4,6,8-tetraenones [9] have been identified by us as potential scaffolds for developing curcumin-based anti-prostate cancer agents because of their apparently improved potency as compared with curcumin. Among them, the 1,4,6-trienone motif was envisioned and illustrated as a good bioisostere of the keto-enol central spacer in curcumin due to the indistinguishable shape and size [8]. Our previous study demonstrates that 1-alkyl-1 H -imidazol-2-yl in compounds 2–6 and 1-alkyl-1 H -benzo[ d ]imidazole-2-yl in compounds 7–11 are significantly beneficial to the in vitro antiproliferative potency in three prostate cancer cell models [8].…”