Structure–Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anticancer Agents

Abstract

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner–Wadsworth–Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure–activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles.

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

“…Curcumin was synthesized by Claisen-Schmidt condensation of aromatic aldehyde with acetylacetone according to the procedure described in the literature [31]. 1-Alkyl-1 H -imidazole-2-carbaldehydes ( 36 - 49 ) and 1-alkyl-1 H -benzo[d]imidazole-2-carbaldehydes ( 60 - 65 ) were synthesized according to the procedure described in the literature [12,13]. …”

“…Extensive research in this field has been conducted by several groups in search for effective curcumin-based anti-cancer agents with favorable safety profiles [10,11]. We have recently identified that (i) 1,5-diheteroarylpenta-1,4-diene-3-ones, exemplified by compounds 2 and 3 in Figure 1, serve as an optimal scaffold for developing potential curcumin-based anticancer agents due to their appreciably enhanced in vitro potency relative to curcumin; and (ii) (1 E ,4 E )-1,5-bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one ( 2 ) is a very promising lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles [12,13]. …”

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 Additionally, in our previous studies, 1-alkyl-1 H -imidazol-2-yl and 1-alkyl-1 H -benzo[ d ]imidazole-2-yl serve as optimal heteroaromatic rings for the antiproliferative potency of 1,5-diheteroarylpenta-1,4-dien-3-ones (e.g. 3 and 4 ) 19 and 1,7-diheteroarylhepta-1,4,6-trien-3-ones (e.g. 5 and 6 ).…”

“…24,25 1-Alkyl-1 H -benzo[ d ]imidazole-2-carbaldehydes ( 27-31 ) were obtained from benzene-1,2-diamine and glycolic acid through a three-step transformation as previously reported by us. 19 Other starting carbaldehydes were purchased from Fisher Scientific. 1,3-Bis(diethylphosphonato)acetone ( 58 ) was readily synthesized from carbazic acid methyl ester, 1,3-dichloroacetone, and triethyl phosphite according to the reported procedure.…”

“…4-16 To overcome its disadvantage (moderate potency and poor bioavailability) as a drug candidate, 6,17,18 chemical manipulations of curcumin have been performed by us and many other research groups. 5,19-21 Consequently, curcumin-based compounds with various lengths of central linkers, including 11-atom linker, 7-atom linker, 5-carbon linker, and 3-carbon linker, have so far been reported to possess similar or increased cytotoxic and anti-proliferative potency against prostate cancer cell lines, as compared with curcumin. 5 However, there is no report available on the curcumin mimics containing a 9-atom linker as anti-prostate cancer agents.…”