Abstract

The aim of this project was to explore the structure-activity relationship (SAR) of novel ferrocenyl based anti-cancer bioconjugates. A series of N-(1’-methyl-6-ferrocenyl-2-naphthoyl) and N- (1’-ethyl-6-ferrocenyl-2-naphthoyl) amino acid and dipeptide esters and a series of N-(ferrocenylmethylamino acid)-fluorinated-benzene carboxamide derivatives have been synthesized, characterized and biologically evaluated for their anti-proliferative activity on various cancer cell lines. The synthesis of each series of compounds was achieved by coupling the free N-terminus of various amino acid and dipeptide esters to the carboxyl group of methyl and ethyl ferrocenyl naphthoic acid or the free N-terminus of the ferrocenylmethylamine to the carboxylic acid group of the N-(fluorobenzoyl)-amino acid using the conventional N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) coupling protocol. All compounds were fully characterized by a combination of spectroscopic techniques, including 1H, 13C and 19F NMR, IR, UV-Vis and MS. Biological evaluation was performed in vitro against the human cervical carcinoma cells (ATCC HTB-35, SiHa) and human liver cells (ATCC CCL-13, Chang liver, HeLa markers) for N-(1’-alkyl-6-ferrocenyl-2-naphthoyl) amino acid and dipeptide esters and vincristine. N-(1’-ethyl-6-ferrocenyl-2-naphthoyl)-glycine-D-alanine ethyl ester had an IC50 of 8.75 μM on cervical cancer cells, which is significantly more cytotoxic than chemotherapeutic medication vincristine. And it has low toxicity against Chang liver cells. The results can suggest that there are differences in susceptibilities to novel ferrocenyl amino acid and dipeptide bioconjugates toxicity between cervical carcinoma and liver cells. Therefore N-(1’-ethyl-6-ferrocenyl-2-naphthoyl)-glycine-D-alanine ethyl ester is a potential anti-cancer agent with selectivity. Another series of N-(ferrocenylmethylamino acid) fluorinated benzene carboxamide derivatives were tested on the estrogen positive (ER+) breast cancer cell line, MCF-7. N-(ferrocenylmethyl-L-alanine)-3,4,5-trifluorobenzene carboxamide, N-(ferrocenylmethyl-L-alanine)-2,3,4,5,6-pentafluorobenzene carboxamide and N-(ferrocenylmethylglycine)-2,3,4,5,6-pentafluorobenzene carboxamide all have strong anti-proliferative effects, with the IC50 values between 0.57-2.14 μM.