Dehydrozingerone, Chalcone, and Isoeugenol Analogues as in Vitro Anticancer Agents

Abstract

Twenty-eight compounds related to dehydrozingerone (1), isoeugenol (3), and 2-hydroxychalcone (4) were synthesized and evaluated in vitro against human tumor cell replication. Except for isoeugenol analogs 27−35, most compounds exhibited moderate or strong cytotoxic activity against KB, KB-VCR (a multi-drug resistant derivative), and A549 cell lines. In particular, chalcone 15 showed significant cytotoxic activity against the A549 cell line with an IC 50 value of 0.6 μg/mL. Furthermore, dehydrozingerone analog 11 and chalcones 16 and 17 showed significant and similar cytotoxic activity against both KB (IC 50 values of 2.0, 1.0, and 2.0 μg/mL, respectively) and KB-VCR (IC 50 values of 1.9, 1.0, and 2.0 μg/mL, respectively) cells, suggesting that they are not substrates for the p-glycoprotein drug efflux pump.Dehydrozingerone (1), isolated from ginger (Zingiber officinale), 1,2 is a well known phenolic natural product with anti-inflammatory, antioxidant, and antitumor promoting activities. 3 It is the structural half analog, as well as biosynthetic intermediate, 4 of curcumin (2), which possesses various remarkable bioactivities such as cytotoxic effects on cancer cell lines 5-8 and induction of apoptotic cell death in human promyelocytic leukemia HL-60 and human oral squamous carcinoma HSC-4 cells. 9 Dehydrozingerone (1), isoeugenol (3) and 2-hydroxychalcone (4) (Figure 1) have similar structures (acetyl, methyl and benzoyl, respectively, attached to a styrene skeleton). Both 3 and 4 are also prominent bioactive compounds. 10,11 Thus, we expected that 1-analogs should show a wide range of pharmacological activities. In spite of the interesting and simple structure of 1, we found only a few literature reports on analog syntheses and structure-activity relationships (SAR), 12,13 although we recently reported the cytotoxic effects of curcumin analogs. 7,14,15 It is known that the presence of a prenyl or geranyl group on flavonoids, including chalcones, can lead to a remarkable increase in bioactivity. 16,17 As dehydrozingerone (1) is structurally related to chalcones, the introduction of a prenyl or geranyl group on any position of 1 might also increase activity. In fact, most prenylflavonoids and geranylflavonoids as well as related compounds are known to have potent cytotoxic effects. 18-21 Furthermore, with respect to cancer research, a prenyl moiety has been demonstrated to be essential for chemopreventive

Trends in Utilization of the Pharmacological Potential of Chalcones

“…The positive control doxorubicin had an IC 50 value of 0.1 µg/ml. The chalcones 57b and 57c showed significant cytotoxic activity against nasopharyngeal carcinoma KB (IC 50 = 1.0 and 1.0 µg/ml) and multidrug-resistant expressing P-gp KB-VCR cell lines (IC 50 = 2.0 and 2.0 µg/ml) suggesting they are not substrates for the P-gp drug efflux pump [76].…”

Chemical composition of the essential oil of aerial parts ofHaussknechtia elymaiticaBoiss. from Iran: a good natural source fortrans-asaron

“…Elution with n-hexane afforded two compounds. Identification of these major compounds was carried out by comparing their 1 H NMR spectra with those reported in the literature (Patra & Mitra, 1981;Tatsuzaki et al, 2006) and also by GC-MS. On the basis of these results, the H. elymaitica's oil could be considered a potential natural source of trans-asarone. Asarones have also shown antibacterial activity.…”

Cytotoxic chalcones and antioxidants from the fruits of Syzygium samarangense (Wax Jambu)

“…The presence of a 4-OH group, and an α, β-unsaturated double bond are essential features for the cytotoxic activity of this class of compound (Cai, Sun, X., Luo & Corke, 2006). In a report on structure activity relationships of chalcones, a series of O-methylated chalcones showed activity against human tumor cell replication (KB, KB-VCR and A 549 cell lines) (Tatsuzaki, Bastow, Nakagawa-Goto, Nakamura, Itokawa & Lee, 2006). Another investigation showed that several ring-A methoxylated chalcones exhibited cytotoxic activity by inhibiting tubulin polymerization against a variety of tumor cell lines in the low micromolar range (IC 50 < 50 μM) (Go, Wu & Liu, 2005).…”