ENHANCEMENT OF THE CYTOTOXIC ACTIVITY OF SOME α,β-UNSATURATED KETONES THROUGH AUXILIARY BINDING
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The antineoplastic properties of α,β-unsaturated ketones, such as curcumin and related analogs, have been investigated for a number of years. Due to the high light sensitivity and the low bioavailability of curcumin and its analogs, there was a need to modify its structural features for clinical usage as a chemotherapeutic candidate. The emphasis on synthetic curcumin analogs which have the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore (Figure 2-1, page 32) and its importance for eliciting antineoplastic activity was made from this laboratory. It was proven that one way these agents exert their activity is through a thiol-alkylating mechanism. In order to increase the cytotoxic activity of these candidate agents, three target compounds containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore were designed by incorporating potential auxiliary binder groups (Figure 2-2, page 33). The auxiliary binders may display antineoplastic properties, or they may act only to enhance the bonding at the binding site. The synthesis of the auxiliary binders and the target compounds containing different physicochemical properties was proposed in order to investigate the structural features responsible for enhancing the biological activity. Both auxiliary binders 1 and the target compounds 2 were synthesized successfully mainly through a series of condensation reactions (Schemes 4-1 and 4-2, pages 61-63). Following the synthesis, the biological evaluation was performed including multiple cytotoxicity assays59-61 as well as a multidrug resistance (MDR)-revertant assay62. The compounds were analyzed via 1H NMR, 13C NMR, and CHN elemental analyses. The biological screening of 1a, 1f, and 1g using four cell lines L1210, Molt4/C8, CEM, and HeLa cells revealed that they lack cytotoxic activity (IC50 > 100 μM, Table 4-1, page 65), and they might play a role in enhancing the alignment of the target compounds to the receptor. However, other auxiliary binders also displayed very low cytotoxicity (IC50 > 100 μM) except for 1h (IC50 = 61 μM). The target compounds 2c (13.3 μM) and 2d (15.3 μM) were more potent than 2b (25.5 μM) in this assay.59 These data are presented in Tables 4-1 and 4-2, pages 65 and 66. The target compounds also displayed anti-metastasis activity towards various non-adherent cancer cells60 indicated on page 81. Generally, the target compounds 2b-d have selectively inhibited tumor growth in the micromolar and sub-micromolar range, and the highest potency was displayed by 2b which inhibited > 50% of non-adherent tumor cells at 1 μM. Two auxiliary binders inhibited more than 10% of the tumor cells at 5 μM namely, 1g (20%, Jurkat) and 1j (32.3%, DU145) respectively. These data are presented in Tables 4-4 and 4-5, pages 69 and 70. The selective cytotoxicity of the target compounds 2b-d as well as the auxiliary binders 1 were also examined.61 Some of the auxiliary binders displayed cytotoxic effects at CC50 < 80 μM namely, 1c, 1f, 1h, 1j, and 1m. Compounds 2b-d displayed potency in the range of CC50 = 14-44 μM; however, 2b is the best candidate compound as it exhibited high selectivity (SI up to > 30.44) to cancer cells compared to 2b and 2c. Moreover the target compounds 2b-d have MDR-revertant properties at low and high micromolar concentrations in which the established FAR values were > 1. Compound 2b reversed the MDR at 50 μM (FAR = 118.15 at 50 μM) more that standard drug verapamil (FAR = 15.68). For future directions, selected auxiliary binders will be incorporated to the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore, and the mechanism of auxiliary binding should be investigated.
DegreeMaster of Science (M.Sc.)
DepartmentPharmacy and Nutrition
SupervisorDimmock, Jonathan R.; Sharma, Rajendra K.
CommitteePalmer, David; Das, Umashankar; Alcorn, Jane; Majewski, Marek
Copyright DateNovember 2012
Curcumin analogs, cytotoxicity, anticancer agents, 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore, multidrug resistance.