Cancer remains one of the leading causes of death in the world, and according to many cancer institutes, there will be a further increase in new cancer incidents and cancer-induced deaths in the near future. Despite significant improvements in the current treatment options such as surgery, radiotherapy, chemotherapy and immunotherapy, the major drawbacks of cancer treatment, e.g. damaging the normal cell while curing the malignant cell, high toxicity and severe side effects of the cytotoxic agents, still pose a great challenge for cancer treatment. Therefore, development of more effective immunogenic or cytotoxic agents, as well as targeted diagnosis and reduction of reoccurrence, call for more intense investigation and research. In this dissertation we have highlighted some recent efforts which have been made in carbohydrate-based cancer treatments specially in vaccine design and development of glycoconjugate prodrugs.
Cancer of diverse origins are predominant in different kind of extracellular tumor-specific carbohydrate antigens (TACAs) because of aberrant glycosylation and role of immunogenic enzymes. However, these B-cell dependent, poorly immunogenic carbohydrate antigens are unable to induce stronger cellular T (cluster of differentiation, CD 4+ and/or CD8+) cell dependent immunity on their own; which is critical for presentation on major histocompatibility class (MHC) molecules of antigen presenting (AP) cells. Over the past few years, several approaches have been designed to overcome the T-cell independent limitation for development of semi- or fully-synthetic, multi-component carbohydrate-based cancer vaccines. The most well-known strategy is conjugation of TACAs with carrier proteins like Tetanus toxoid (TTox), Keyhole limpet hemocyanin (KLH), Bovine serum albumin (BSA), but most of them suppressed the antigenic immunogenicity. However, as an alternative to use of proteins and inspired by the immunogenicity of a zwitterionic polysaccharide, PS A1, our group has synthesized several immunogens by bio-conjugating PS A1 with some tumor associated carbohydrate antigens (TACAs) via oxime linkage. This polysaccharide was isolated from an anaerobic bacteria (B. fragilis ATCC 25285/NCTC 9343), consists of a tetra-saccharide repeating unit (120 repeating units, MW of ~110 KDa), and is known to exhibit MHC II mediated T-cell immune response. Furthermore, we selected an epitope of MUC1 which is reported to be processed by AP cells and presented to MHC class I, essential for activation of cytotoxic T-cells (CD 8+ T-cells). Therefore, we conjugated it with PS A1, with the aim of generating a Tn specific immune response mediated by both MHC class I and II. Tn-PS A1, MUC1-PS A1 and Tn-MUC1-PS A1 vaccines have been synthesized to compare their immunogenicity.
Tumor cells get more energy for proliferation than normal cells by consuming excessive amounts of glucose via overexpressed sugar binding or transporting receptors located in the cellular membrane. Because of this distinguishable feature between normal and tumor cells, those sugar receptors are considered as biomarkers for cancer detection and have always been prioritized for the development of novel cancer therapeutics. Furthermore, inspired by the Warburg effect, glycoconjugation strategies of anticancer drugs have gained considerable attention in the scientific community. This strategy improves the pharmacokinetics properties, selectivity of cytotoxic aglycons and very useful for targeted drug delivery.
Malformin C, a bicyclic penta-peptide, originally isolated from Aspergillus niger fungal strains, can induce various biological effects including root curvatures, malformations in plants, antibacterial activity against gram-positive and gram-negative bacteria, anti-fibrinolytic activity and inhibitory activity on the G2 checkpoint of the cell cycle. Researchers have found that the malformin family can influence biological effects even their subtle structural differences on the noted amino acid side chains. Therefore, total synthesis of malformin C, malformin A1 and an analog was carried out with improved strategies to avoid unwanted side reactions.
In order to have a more effective drug, it is necessary to synthesize more potent anti-cancer reagent and analogs thereof to improve therapeutic efficacy. Overexpression of GLUT-1, mostly a glucose transporter, observed by many studies in carcinomas such as lung, liver, gastric, pancreas, colorectal, brain, breast, erythrocytes is possibly the reason of elevated glucose uptake by cancerous cells. Therefore, we have synthesized a glucose conjugated with malformin C assuming it will penetrate through the cell membrane via GLUT-1 transporter. Resulting enhanced delivery of the active drug targeting tumor cells more specifically and the potency for reduced side-effects.