Studies of an ortho- Formylation Reaction and its Application for the Syntheses of Anti-Cancer Agents

Abstract

Recently caspases have received much attention as potential drug targets in the treatment of cancer. Procaspase-3, the executioner of apoptosis, was found to be in elevated concentrations in cancer cells. Procaspase activating compound 1, PAC-1, induced cell death through activation of caspases in a dose dependent manner in cancer cell lines. This prompted us to synthesize 16 PAC-1 analogues which were tested for their cytotoxic properties in seven cancer cell lines. Two compounds, 128 and 130, were equally cytotoxic as PAC-1 in the PC12 cell line. PAC-1 was investigated for its toxicity in non-dividing cells; chicken granular neurons, and was established as a potential neurotoxin. The ortho-formylation reaction employing the MgCl2/Et3N base system has been well established as a versatile and environmental benign method. This base system have been employed in the syntheses of salicylaldehydes, one-pot procedures and total synthesis of natural products. The original ortho-formylation method article by Skattebøl and Hofsløkken has close to 100 citations. We have explored the reaction conditions on mono-protected resorcinols and estrogens. In both compound classes, good to high yields were obtained, as well as regioselectivity. The ortho-formylation of estradiol was used as a key step in the preparation of the anti-cancer agent 2-methoxyestradiol. The phosphate prodrugs of combretastatin A-1 and A-4 are currently in human clinical trials for their anti-cancer properties. Even though the solubility problems the combretastatins first faced have been solved now, there is still an issue with the isomerization of the cis-olefinic bridge to the inactive trans-isomers of the combretastatins. Our laboratory has successfully replaced the bridge with the heterocyclic moiety 1,2,3-triazole to produce cis-restricted analogues of CA-1. The analogues were subjected to cytotoxicity testing against four cancer cell lines and evaluated for their anti-angiogenetic properties. The most cytotoxic triazoles were also tested for their ability to inhibit tubulin polymerization. Compound 180 showed equal potency as CA-1 (19) in all the cell lines and was equally active as a inhibitor of tubulin polymerization and angiogenesis. These activities are most likely, at least in part, due to binding to the colchicine binding site of a,ß-tubulin, as supported by molecular modeling studies.