The therapeutic role of modified saccharide in an in vitro human colon cancer model

Hybrid molecules, formed by chemically combining two or more distinct bioactive molecules or pharmacophores, are highly valued for their potential to enhance the efficacy of existing treatment regimens and reduce toxicity. Hybrid molecules designed for colorectal cancer, the third most common type of cancer worldwide and in our country, are particularly significant for improving treatment efficacy and reducing the severe side effect profile associated with conventional therapies. This thesis aims to develop lead compounds as alternatives to current anticancer treatment regimens by utilizing natural bioactive phytochemical compounds such as glucosamine, vanillic acid, and indole-2-carboxylic acid. In this context, hybrid molecules SI-2 and SI-4 were synthesized using glucosamine, vanillic acid, and indole-2-carboxylic acid, and their structural characterizations were performed using 1H-NMR, FTIR, and LC/MS analyses. The structural analysis results confirmed the successful synthesis of SI-2 and SI-4. The anticancer functions of these molecules were evaluated through in vitro MTT assays using the human colon adenocarcinoma HT-29 cell line, and IC50 values were calculated using GraphPad Prism-8. The hybrid molecules SI-2 and SI-4 demonstrated cytotoxic effects and anticancer properties against HT-29 cells. After 24, 48, and 72 hours of incubation, the IC50 values were determined as 116,40 μM, 33,54 μM, and 13,19 μM for SI-2, and 103,20 μM, 75,90 μM, and 42,69 μM for SI-4, respectively. For OX, a drug used in the conventional treatment of colorectal cancer, the IC50 values after the same incubation periods were found to be 1283 μM, 42,98 μM, and 17,60 μM, respectively. Furthermore, combinations of the hybrid molecules with OX were evaluated using the Chou-Talalay method. For the SI-2+OX and SI-4+OX combinations, the IC50, IC50/2, IC50/4, IC50/8, IC50/16, and IC50/32 doses were assessed after 48 hours of exposure. The combination index (CI) values for SI-2+OX were 1,74, 1,01, 0,70, 0,65, 0,31, and 0,26, while for SI-4+OX, the CI values were 0,80, 0,47, 0,25, 0,39, 0,29, and 0,21, respectively. The dose reduction index (DRI) values for OX in the SI-2+Oxaliplatin combination were 1,51, 2,46, 3,18, 2,87, 6,13, and 6,31, while for the SI-4+OX combination, they were 7,78, 11,95, 21,01, 7,70, 8,64, and 10,34, respectively. These combinations demonstrated synergistic effects. In addition, OX, a key component of current treatment regimens, is associated with a severe side effect profile. The high DRI values observed for OX in the 48-hour exposure of the combinations suggest a potential reduction in its side effect profile. In this context, both molecules have demonstrated unique potential as lead candidates for the development of anti-colon cancer drugs in humans.