Bisphosphonates have been used as effective treatments for various diseases associated with increased bone resorption, including osteoporosis, Paget's disease, multiple myeloma, metastatic bone disease. Its structure has a significant influence on efficacy and relative utility in managing specific disorders of bone resorption. In order to investigate structure-function relationship of bisphosphonate derivatives and develop new antiresorptive drug, this study has investigated new conjugates of bisphosphonate and porphyrins. In this thesis, we report the synthesis, characterization, bioactivity of these conjugates. The following are the main results reported in this thesis work:...[ Read more ]

Bisphosphonates have been used as effective treatments for various diseases associated with increased bone resorption, including osteoporosis, Paget's disease, multiple myeloma, metastatic bone disease. Its structure has a significant influence on efficacy and relative utility in managing specific disorders of bone resorption. In order to investigate structure-function relationship of bisphosphonate derivatives and develop new antiresorptive drug, this study has investigated new conjugates of bisphosphonate and porphyrins. In this thesis, we report the synthesis, characterization, bioactivity of these conjugates. The following are the main results reported in this thesis work:

1. Two new bisposhonate modified water soluble porphyrins, 18 and 19 have been synthesized and characterized by ¹H-NMR, ³¹P-NMR, MS and UV-Vis Spectroscopy.

2. Binding constants of 4 different imidazole-base ligands, two of them being bisphosphonate derivatives (23 and 24) of water-soluble zinc meso-tetra-(4-N-methyl pyridyl)porphyrin iodide (4), have been determined by photometric titration. Zoledronate (23) was found to have the highest binding constant of 12303 M^-1.

3. The cytotoxicity of two imidazole-based bisphosphonates (23 and 24) with water-soluble porphyrin (4) towards osteoblast was compared with bisphosphonate modified porphyrin (18 and 19). It can be seen that there is no significant toxicity of bisphosphonate modified porphyrin (Figure 19, 22, 25 and 26). Zoledronate binding to porphyrin 4 has lower toxicity towards osteoblast when compared with zoledronate alone (Figure 19), and this effect only occurs at high concentration.

4. There is no significant PDT effect of 18 towards HeLa cell. It has significant dark toxicity towards this cell line. However 18 is biocompatible with osteoblast (Figure 25) when compared with pamidronate. Therefore, 18 has a selectivity between normal cell and tumor cell, or at least between tumor HeLa cell and osteoblast.