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Synthesis and bioactivities of novel N¹-acylhydrazides



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Curcumin, a herbal polyphenol, has demonstrated anticancer activity in vitro as well as in vivo but have limited clinical benefits due to low oral bioavailability. Structural modification such as truncation of the β-diketone moiety of curcumin led to the development of the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore and its importance in displaying antineoplastic properties has been demonstrated by our laboratory. In light of this concept, this thesis focuses on the design and development of novel 3,5-bis(benzylidene)-1-[3-(arylcarbonylaminoamino)-3-oxo-1-propyl]-4-piperidones 64a-g having two pharmacophores, namely, the 1,5-diaryl-3-oxo-1,4-pentadienyl moiety which is believed to act at the primary binding site and N¹-acylhydrazides 60a-m which are considered to be the auxiliary binders. The biological screening reveals that the auxiliary binders 60m (IC50 = 15.27 µM in HCT 116 cells) and 60l (IC50 = 3.18 µM in MCF-7 cells) were the most potent cytotoxins in series 60. The evaluation of druglike properties revealed that 64a is the lead tumor-specific cytotoxin with an IC50 value of 1.38 µM against HCT 116 cells. When compared against colon CRL-1790 non-malignant cells, these cytotoxic agents (60a, 60m, 63a and 64a-g) and 60j-l showed greater selective toxicity towards colon HCT 116 cells and breast MCF-7 cells, respectively. (Tables 5.2, 5.3 and 5.5). The combinatorial study indicated that 60m is a chemosensitizer towards HCT 116 cells to 3,5-bis(benzylidene)-4-piperidone 63a and the reference drug 5-fluorouracil (Table 5.8, 6.2). When screened against various human oral carcinoma and normal cell lines, 63a has shown potent cytotoxicity (CC50 < 0.46 µM) and 60a, 60d and 60l showed moderate activity (CC50 in range of 46-47 µM) (Table 5.9). Four auxiliary binders 60a, 60d, 60h and 60l displayed excellent cytotoxicity in the range of 0.15-5.62 µM when screened against various adherent and non-adherent leukemic cells (Table 5.10). All four compounds displayed high cytotoxic potency and greater selectivity towards Ramos leukemic cells with 60h being the most potent with an IC50 value of 0.15 µM and 60l being highly selective with a selective index value greater than 90. The cytotoxic effects of the auxiliary binder 60l (in Ramos leukemic cells) and target compounds 64a, 64e and 64g towards HCT 116 cells might be due to decreasing the mitochondrial membrane potential and a 2-4 fold increase in the reactive oxygen species levels (60m, 64a, 64e and 64g in HCT 116 cells), as suggested by mechanistic investigations.



Curcumin, 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore, N¹-acylhydrazides, Chemosensitizer, Mitochondrial membrane potential, Reactive oxygen species



Master of Science (M.Sc.)


Pharmacy and Nutrition




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