Design, synthesis, and evaluation of novel heteroaromatic analogs of curcumin as anti-cancer agents

Abstract

To improve the potential of curcumin to treat advanced hormone-refractory prostate cancer, three series (A–C) of heteroaromatic analogs (thirty two compounds) with different monoketone linkers have been synthesized and evaluated for cytotoxicity against two human androgen-independent prostate cancer cell lines (PC-3 and DU-145). Among them, thirty analogs are more potent than curcumin against PC-3 cells, and twenty one analogs are more cytotoxic towards DU-145 cells relative to curcumin. The most potent compounds (44, 45, 51, and 52) also showed impressive cytotoxicity against three other metastatic cancer cell lines (MDA-MB-231, HeLa, and A549), with IC50 values ranging from 50 nM to 390 nM. All four most potent analogs exhibited no apparent cytotoxicity towards the MCF-10A normal mammary epithelial cells. Taken together, selective enhancement of cell death in prostate cancer cell lines and other aggressive cancer cell lines suggests that nitrogen-containing heteroaromatic rings are promising bioisosteres of the substituted phenyl ring in curcumin.

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]. …”

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

“…According to the procedure described in the literature, 21 the potassium carbonate-mediated double aldol condensation of the appropriate aromatic aldehyde with acetone was employed to successfully synthesize eleven 1,5-diheteroarylpenta-1,4-dien-3-ones in our previous study. 18 However, most of target compounds for the current study were hard to obtain through the base-catalyzed aldol condensation. After various explorations, we eventually succeeded in synthesizing compounds 6–48 in good yields through the Hornor–Wadsworth–Emmons reaction of 1,3-bis(diethylphosphonato)acetone with the appropriate aromatic aldehyde 22 (Scheme 1).…”

“…Encouraged by the potency conferred by the linear dienone linker and the basic aromatic rings, 18 we set out to explore the effect of various heteroaromatic rings on the cytotoxicity of 1,5-diheteroarylpenta-1,4-dien-3-ones against prostate and cervical cancer cell lines. Consequently, forty-three compounds ( 6–48 , Table 1 and Scheme 1) containing two identical terminal five-membered, six-membered, or bulky heteroaromatic rings and a central dienone linker have been designed and synthesized as curcumin mimics for cytotoxic and antiproliferative evaluation.…”

“…17 Our previous preliminary data showed that 1,5-diheteroarylpenta-1,4-diene-3-ones, represented by compounds 3–5 , is an optimal scaffold for developing curcumin mimics as potential anticancer agents due to their superior in vitro potency (up to 60 times better than curcumin) and potential pharmacokinetic profiles. 16,18 This scaffold of curcumin mimics 16,18 is characteristic of two identical terminal five- or six-membered heteroaromatic rings and a central linear dienone linker. They consistently exhibit enhanced cytotoxic potency than curcumin in androgen-insensitive prostate cancer cell lines (PC-3 and DU-145) but no apparent toxicity against MCF-10A normal mammary epithelial cells.…”