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Recently the Peterson lab discovered a promising anticancer adenosine derivative-- 2´,3´-bis-O-tert-butyldimethylsilyl-5´-deoxy-5´-[N-(methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine. This compound showed selective toxicity against human colon cancer cells in vitro with LC50's = 6--10 µM. It was hypothesized that the lead compound exerted its cytotoxic effects by interacting with a protein kinase. A systematic Structure Activity Relationship (SAR) was undertaken in an attempt to increase the kinase-binding affinity of the lead compound. Many regions of the lead compound were examined: the N6-phenyl urea moiety, the 5´-N-methyl urea group, the 2´,3´-bis-O-TBS groups, the nucleobase, and the ribose sugar. Results of these studies produced some promising new derivatives. In particular, one analogue exhibited potent cancer cell growth inhibition with an average GI50 of 0.58 μM (NCI-60). In addition, another compound showed selective toxicity for the non-small cell adenocarcinoma cell line NCI-H522 with an LC50 of 10 nM. Efficient methods for the preparation of a wide variety of N6-aryl and -alkyl substituted derivatives were developed. One versatile route involved the installation of an N6-ethoxy carbonyl and subsequent displacement with an alkly- or arylamine. Synthetic routes for the preparation of of a variety of 2´,3´-bis-O-acylated analogues were also developed. Nucleoside mono-, di-, and triphosphate bioisosteres in which the phosphoester or phosphoanhydride have been replaced by an unnatural functional group have been extensively investigated. A simple and efficient method was developed for the preparation of carbamoyl analogues of nucleoside mono-, di-, and triphosphate surrogates. This method uses a modified version of the Kočovský reaction to install mono-, di-, and triphosphate mimics in good to excellent yields (ave = 75%).

<p>  </p> <p>Quinolines are benzopyridine complexes present in many modern antimalarial, anticancer, anti-inflammatory, antimicrobial, and other useful pharmaceuticals and natural products.1,2 Quinolines form the scaffold for many potent anticancer drugs; this is because quinolines can undergo both nucleophilic and electrophilic substitution reactions, can be ingested and inhaled by humans without any harm, and possess a great deal of biological importance.3 My research has focused on synthesizing 3H-pyrazolo[4,3-f]quinoline analogs. The 3H-pyrazolo[4,3-f]quinoline scaffold was modified using various amine groups to obtain amide analogs as well as see how a change in the scaffold affects the anticancer activity of the synthesized complexes by screening them against kinases such as FLT3, CDK2, CDK4, and CDK9 to see if they are effective inhibitors. The synthesized complexes were then characterized using proton, carbon NMR and FTIR spectroscopy.</p>

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Solid tumors possess biological features that are different from those in healthy tissues, which provides opportunities of anticancer treatment by nanomedicines. Due to the presence of the fenestrated tumor vasculatures, nanomedicines can selectively accumulate in tumor tissues by the enhanced permeability and retention (EPR) effect. The acidic pH in tumor interstitium (pH 6.0-7.0) also provides a promising mechanism to trigger the nanomedicines to promote the cellular uptake of cargo drugs. The previously reported stealth liposomes coated with PEG are known to accumulate in tumors owing to their prolonged circulation time. The PEG coating on liposomes can hinder serum protein adsorption and thus prevent rapid elimination by the reticuloendothelial system, thus increasing the liposome circulation time. However, liposomal interaction with cancer cells can also be hindered by the PEG coating. In order to improve the anticancer activity of stealth liposomes, novel synthetic imidazole-based lipids were introduced to the composition of stealth liposomes to develop the pH-sensitive imidazole-based convertible liposomes (ICL). At acidic pH, the imidazole-based lipids would protonate to acquire positive charges, thus clustering with the negatively charged PEGylated lipids. Such lipid-lipid electrostatic interaction would induce phase separation of the bilayer to generate a PEG-free domain that displays excess positive charges. Such newly converted, cationic liposomes at acidic pH in tumor interstitium would have better interaction with negatively charged cancer cells and/or enhanced drug release, therefore overcoming the drawback of traditional stealth liposomes. After synthesizing the imidazole-based lipids DHI, DHMI and DHDMI, we constructed doxorubicin (DOX)-loaded ICL formulations. The physicochemical properties of ICL were characterized, and factors influencing such properties were explored. The pH-triggered acquisition of positive charges of ICL was confirmed by the elevation of ζ- potentials and aggregation with negatively charged model liposomes that mimic bio-membranes at acidic pH 6.0-7.0. Acidic pH-triggered release of ICL was confirmed by drug release assays. It was also found that although the incorporation of cholesterol can remarkably reduce the size and increase the encapsulation efficiency (EE) of ICL, it also hinders the pH-sensitivity of ICL. The morphology of ICL at both pH 7.4 and pH 6.0 was characterized under transmission electron microscopy (TEM), which showed morphological changes in response to acidic pH 6.0, which further supported the proposed pH-sensitivity of ICL. Cytotoxicity assays on 3D MCS of HeLa, A549, MDA-MB-231 and MDA-MB-468 cell lines were conducted to evaluate the anticancer activity of ICL formulations. ICL formulations without cholesterol showed considerably enhanced anticancer activities against MCS compared with the non-sensitive stealth liposomes (NSL). However, incorporation of cholesterol decreased such activities. The IC50 values of cholesterol-free ICL and ICL with cholesterol against MCS strongly suggested that the pH-sensitivity introduced by the imidazole-based lipids would enhance the anticancer activity of stealth liposomes, while the hindrance of the pH-sensitivity by cholesterol would reduce such activities. Taken together, ICL’s pH-sensitivity is correlated with their enhanced anticancer activity than non-sensitive stealth liposomes.

Methotrexate (MTX) is an antimetabolite anticancer agent that is used in treatment of multiple cancers, such as acute lymphoblastic leukaemia and osteosarcoma. A lack of selective tumour toxicity is one of the major problems associated with MTX chemotherapy, especially when given at high doses, as in high dose MTX (HDMTX) therapy. MTX causes various toxicity problems including life-threatening nephrotoxicity, haematological toxicity and neurotoxicity. Overcoming this toxicity is of great importance and has been attempted in various ways, not least via the design of prodrugs. The concept of tumour protease, and specifically matrix metalloproteinase (MMP), activated prodrugs was the focus of the work described in this thesis. This concept relies upon attachment of an MMP-sensitive peptide sequence to a specific site in a drug structure, so as to inactive it. The activity of the parent drug is restored once it is activated by the MMPs in the tumour microenvironment. In this work, different MMP-sensitive peptide sequences linked to MTX were synthesised, resulting in 63 MTX prodrugs. The MMP-mediated activation of these conjugates in tumour tissues (specifically HT1080 homogenates) ex vivo was assessed and the results were compared to the activation of these conjugates in various normal tissues specifically liver, kidney and lung. Specific criteria were established for the selection of promising conjugates for more detailed study. From 7 promising compounds, compound 75 was identified as the lead prodrug, demonstrating selective MMP activation, as indicated by inhibition of its activation by broad spectrum MMP inhibitor ilomastat. The pharmacokinetics of compound 75 was studied in tumour (HT1080) xenograft-bearing mice and the results were compared to those obtained from administration of equimolar doses of conventional MTX. Compound 75 led to enhanced tumour concentrations of MTX, with reduced exposure to normal tissues in vivo compared to conventional MTX therapy. Furthermore, the efficacy of equimolar doses of compound 75 and directly dosed MTX in reduction of HT1080 volume were compared. Superior antitumour activity was observed with compound 75 compared to MTX treatment. Compound 75 is the first example of an MMP-activated prodrug to be reported with enhanced therapeutic index, as evidenced by a full in vivo pharmacokinetic analysis and normal tissue metabolism data. The data presented in thesis support the concept of MMP-activated prodrug development, and form a strong foundation upon which to develop a clinically-useful MTX prodrug, with the potential to enhance efficacy and reduce toxicity to the patient. / Libyan government / The full text will be available after the extended embargo: 5th March 2027

The aldehyde dehydrogenase (ALDH) superfamily is gaining momentum in regard to stem cell and cancer research. However, their regulation and expression in the cancer microenvironment is poorly understood. The aim of this work was to understand the role of selected ALDH isoforms (1A1, 1A2, 1A3, 1B1, 2, 3A1 and 7A1) in colorectal cancer (CRC) and explore the impact of hypoxia on their expression. CRC cell lines (HT29, DLD-1, SW480 and HCT116) were grown under normoxic or hypoxic conditions (0.1% O2) and HT29 and DLD-1 in spinner flasks to generate multicellular spheroids (MCS). Hypoxia was demonstrated to have an impact on the ALDH expression, which appeared cell-specific. Notably, ALDH7A1 was induced upon exposure to hypoxia in both HT29 and DLD-1 cells, shown to be expressed in the hypoxic region of the MCS variants and in 5/5 CRC xenografts (HT29, DLD-1, HCT116, SW620, and COLO205). ALDH7A1 siRNA knockdown studies in DLD-1 cells resulted in significant reduction of viable cells and significant increase in ROS levels, suggesting ALDH7A1 to possess antioxidant properties. These findings were further supported using isogenic H1299/RFP and H1299/ALDH7A1 lung cancer cell lines. ALDH7A1, however, was found not to be involved in inhibiting the pharmacological effect or causing resistance to different cytotoxic and molecularly targeted anticancer drugs. To unravel the functional role of ALDH7A1, 9 compounds obtained from a virtual screening of 24,000 compounds from the Maybridge collection of compounds were used to probe ALDH7A1 functional activity. One compound, HAN00316, was found to inhibit the antioxidant properties of ALDH7A1 and thus could be a good starting point for further chemical tool development. Although this study underpins a potential important role of ALDH7A1 in hypoxic CRC, further work is required to fully validate its potential as a biomarker and/or pharmacological target. / Jordan University of Science and Technology

The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC50 values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate.