Electronic Theses and Dissertations
Permanent URI for this community
Browse
Browsing Electronic Theses and Dissertations by Subject "1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Cytotoxic thiol alkylators containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore(2012-09-06) Das, Swagatika; Dimmock, Jonathan R.; Gorecki, Dennis K.; Bandy, Brian; Nazarali, Adil; Sanders, DavidFor the last several years curcumin has attracted considerable interest due to its ability to inhibit cancer cell proliferation in vitro and in vivo by targeting a number of different cell signaling and molecular mechanism pathways in cancer cells. These results prove its potential to be considered as a future anticancer drug candidate. However its metabolic instability, low oral bioavailability and high clearance have limited its use as a clinical drug candidate. Subsequently enormous efforts have been expended by medicinal chemists to modify the curcumin structure which has led to the development of novel cytotoxic curcuminoid analogs. The replacement of the β-diketone moiety by a mono carbonyl group led to the discovery of the 1,5-diaryl-3-oxo-1,4- pentadienyl pharmacophore which was found to be metabolically stable and demonstrate high cytotoxic potencies. This class of compounds which possesses multiple alkylating sites are referred to as thiol alkylators based on their ability to interact preferentially with the thiol groups of macromolecules compared to the hydroxy and amino groups present in nucleic acids. The ability of this class of compounds to target multiple biochemical pathways has been considered to be an advantage to overcome multidrug resistance that is shown by many tumours to current anticancer drugs. My current work in this report focuses on the development of novel curcuminoid analogs possessing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore as potent cytotoxic agents with the aspiration of identifying some lead molecules which can further be developed as anticancer drug candidates. In particular, the synthesis of novel curcuminoids based on the 3,5-bis(arylidene)-4-piperidone nucleus is pursued. One of the main objectives was to produce novel cytotoxins which will display selective toxicity towards malignant cells compared to normal cells. In order to obtain tumour-selective cytotoxins, the design of molecules was based on a theory of sequential cytotoxicity which states that an initial chemical attack on cellular constituents followed by a second chemical attack will cause more damaging effects in cancer cells than normal cells. The sequential alkylation reaction was proposed to take place on both of the olefinic carbon atoms of the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore in the molecules at the primary binding site whereas the other part of the molecule would interact at an auxiliary binding site which may confer preferential toxicity to tumours. Efforts have been made to improve the physicochemical properties of the molecules by introducing hydrophilic groups such as phosphates onto the molecules. Bioevaluations of the novel molecules disclosed in the thesis revealed that many of these compounds display potent cytotoxic properties towards a wide range of neoplastic and transformed cells and show greater cytotoxic potencies to neoplasms than normal cells. Most of the molecules demonstrated higher cytotoxic potencies and greater tumour selectivity than melphalan, a reference alkylating anticancer drug. In general, increasing the number of thiol alkylating sites in the molecule has increased cytotoxic potencies and selective toxicities to tumours compared to normal cells. One of the major challenges in cancer treatment is the resistance shown by tumors towards a number of chemotherapeutic agents. The molecules designed in this report are chemically and structurally divergent from established anticancer drugs; therefore they are expected to display different modes of action and may be able to overcome drug resistance shown by tumours to contemporary anticancer agents. The ability of novel cytotoxic agents to modulate P-glycoprotein mediated drug resistance, a major form of drug resistance in cancers, was verified in a neoplastic cell transfected with the mdr1 gene. A number of molecules demonstrate remarkable multidrug resistance reversal properties in a neoplastic cell line and the aspiration is that one or more molecules can be developed as a potent multidrug resistance modulator. A striking feature of many of these curcuminoids is that using a dose level up to and including 300 mg/kg is well tolerated in mice and displays no significant toxicities. The modes of action of a number of representative potent cytotoxic molecules were evaluated which include apoptosis, caspase-3 activation, DNA fragmentation, PARP cleavage and cell cycle arrest. The mitochondrion is emerging as a potential target for anticancer agents and to evaluate this possibility, the effect of a number of potent cytotoxins on mitochondrial functions was verified. The compounds affected respiration and caused swelling in mitochondria. Some guidelines for future development of these molecules are suggested. It is hoped that this eulogy of the importance of the conjugated dienone group will encourage researchers to consider incorporating this structural unit into candidate cytotoxins.Item Synthesis and bioactivities of novel N¹-acylhydrazides(2018-09-25) Lakhani, Kinjal Murad; Dimmock, Jonathan R; Sharma, Rajendra; Blackburn, David; Sanders, David; Lee, JeremyCurcumin, 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.