Chalcones are widely explored as potential lead compounds for new drugs, including antitumor medicaments [1-10]. In vitro cytotoxicity of most of chalcone derivatives is in 1 – 50 micromolar range. Now we found that chalcones bearing a fused oxathiole ring (1 or 2) display cytotoxic activity even in a nanomolar range, e.g. for compound AMG-304 (5, R = CH₃, X = 4-OCH₃, Y = 3-OH), IC₅₀ = 10 nM (A549) and 5 nM (HeLa).

Change of the ring size from five to a six membered one (3, 4) does not influence much the activity, while opening of the heterocyclic ring (5, 6) or its substitution in the position 2 with oxygen (7, 8) diminish the activity (Figure 1).

Figure 1.

Oxidation of isomer 1 to sulfoxide (9) or sulfone (10) result in decrease in cytotoxicity, while analogous oxidation of isomer 2 lead to derivatives 11 and 12 with increased cytotoxic activity (Figure 2).

Figure 2.

The results suggest, that either the relatively small modifications result in change of the mechanism of the cytotoxicity, or structure of the “left hand part” of the molecules is extremely important for interaction of the compounds with target.

Activity of the compounds was also influenced by radical R in the OR alkoxy group, and by substituents X and Y. No simple relationship exist between the influence of the listed structural factors on the cytotoxic activity in vitro of different chalcones.

Cytotoxic activity of chalcones is often associated with their effect on polymerization of tubulin. For this reason inhibition of tubulin polymerization and inhibition of ³H-colchicine binding to tubulin by selected AMG chalcones were studied. Next, the obtained values were correlated with cytotoxicity (Table 1).

Table 1.

nd – not determined

The comparison revealed that there is no correlation between cytotoxicity and inhibition of tubulin polymerization, or colchicine binding.

References.

1. Dimmock, J.R.; Elias, D.W.; Beazely, M.A.; Kandepu, N.M. Curr. Med. Chem. 1999, 6, 1125-1149; Bioactivities of Chalcones.
2. Ni, L.; Meng, C.Q.; Sikorski, J.A.. Expert Opin. Ther. Patents, 2004, 14, 1669-1691; Recent advances in therapeutic chalcones.
3. Go, M.L.; Wu, X.; Liu, X.L. Curr. Med. Chem. 2005, 12, 483-499; Chalcones: An Update on Cytotoxic and Chemoprotective Properties
4. Lawrence, N.J.; McGown, A.T. Curr. Pharm. Design, 2005, 11, 1679-1693; The Chemistry and Biology of Antimitotic Chalcones and Related Enone Systems.
5. Nowakowska, Z. Eur. J. Med. Chem. 2007, 42, 125-137; A review of anti-infective and anti-inflammatory chalcones.
6.  Boumendjel, A.; Ronot, X.; Boutonnat, J. Curr. Drug Targets, 2009, 10, 363-371; Chalcones Derivatives Acting as Cell Cycle Blockers: Potential Anti-Cancer Drugs?
7. Katsori, A-M.; Hadjipavlou-Litina, D.. Curr. Med. Chem. 2009, 16, 1062-1081; Chalcones in Cancer: Understanding their Role in Terms of QSAR.
8. Batovska, D.I.; Todorova, I.T. Curr. Clin.Pharmacol. 2010, 5, 1-29; Trends in Utilization of the Pharmacological Potential of Chalcones.
9. Katsori, A-M.; Hadjipavlou-Litina, D. Expert Opin. Ther. Patents, 2011, 21, 1575-1596; Recent progress in therapeutic applications of chalcones.
10. Sahu, N.K.; Balbhadra, S.S.; Choudhary, J.; Kohli, D.V. Curr. Med. Chem. 2012, 19, 209-225; Exploring Pharmacological Significance of Chalcone Scaffold: A Review.

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