Executive Summary : | Corroles are lipophilic macrocycles and with 18-pi aromatic system. The project is designed to construct a library of water soluble corrole-metal complexes linked to the sugars units. Their synthesis, characterization, photo-physical and biological studies will be part of this project work. In this project the ribose / hexose sugars will be linked to the corrole meso-aryl positions (Scheme 1 and 2); it will solve two issues: (i) it will make the corrole ring hydrophilic; (ii) it will increase the affinity of the corrole towards cancer cells. The tumor cells have been shown to have high affinity for sugar substituted organic molecules due to high rate of cell division. The Gallium, Tin and Rhodium complexes of water soluble corroles will be synthesized (Scheme 2); the heavy metal will help to increase the intracellular ROS (reactive oxygen species) generation. The corrole-sugar conjugates can be used for cell imaging applications and also as sensitizers for PDT (Photo-Dynamic therapy) to treat cancer. The corroles will be conjugated with estradiol group, as the estradiol receptors (ER) are present on the breast cancer cells with different linker length (Schemes 3 and 4). Water soluble corroles linked to estradiol (Scheme 5), will serve as better candidates for intracellular imaging and for the diagnosis of the early stage of tumor, particularly the breast cancer. In-vitro receptor specific assay and MTT assways (cytotoxicity in normal + cancer cells) both in dark and light conditions will be carried out for the metallo-corrole-drug conjugates. After cytotoxicity studies, the potent sugar-corrole-estradiol molecules will be screened for Ex-vivo 3D cellular models studies for cancer progression assays in dark and light conditions. The proposal will try to address the following points: (a) The poor solubility of corrole–metal complexes will be resolved by attaching the sugar units on the corrole’s meso-aryl rings. (b) The combination of sugar units and estradiol moiety will make these drug-conjugates amphiphilic in nature, making them soluble in organic solvents as well as in water. (c) The estradiol moiety will provide desired selectivity to the corrole-drug conjugates towards breast cancer cells as compared to normal cells. Estradiol moiety can have better binding with ER-alpha receptors of breast cancer cells. (d) The glucose/ galactose sugars help to increase the cellular uptake of Metallocorrole-drug conjugates in cancer cells, as they can bind to carbohydrate binding proteins (lectin) overexpressed in cancer cells. (e) The proposed sugar-corrole-estradiol conjugates are “3rd Generation Photosensitizers” which are ideal for diagnosis and anti-cancer treatment. Metallocorrole unit will act as fluorescent tag (bio-imaging agent) with strong absorption and emission in visible-red region. |