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The synthesis, structural characterization and in vitro anticancer activity of novel ferrocenyl bioconjugates

Harry, Andy Garry (2013) The synthesis, structural characterization and in vitro anticancer activity of novel ferrocenyl bioconjugates. PhD thesis, Dublin City University.

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Abstract

A series of 1-alkyl-1’-N-para, N-meta and N-ortho-(ferrocenyl) benzoyl dipeptide esters and N-{para-(ferrocenyl) ethynyl benzoyl}, N-{6-(ferrocenyl) ethynyl-2-naphthoyl} and N-{5-(ferrocenyl) ethynyl-2-furanoyl} amino acid and dipeptide esters were prepared. The novel ferrocenyl based bioconjugates were prepared by coupling 1-alkyl-1’-N-para, N-meta and N-ortho-(ferrocenyl) benzoic acid and N-{para-(ferrocenyl) ethynyl benzoyl}, N-{6-(ferrocenyl) ethynyl-2-naphthoyl} and N-{5-(ferrocenyl) ethynyl-2-furanoyl} benzoic acid to α-amino acid ethyl esters and dipeptide ethyl esters using the conventional N-(3-dimethylaminopropyl)-N’-ethylcarbodiimidehydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. The new classes of compounds were characterized by a combination of 1H NMR, 13C NMR, DEPT-135 and 1H-13C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS). Biological evaluation of the 1-alkyl-1’-N-para, N-meta and N-ortho-(ferrocenyl) benzoyl dipeptide esters were carried out in the H1299 non-small cell lung cancer (NSCLC) cells. The most active derivatives of the 1-alkyl-1’-N-para, N-meta and N-ortho-(ferrocenyl) benzoyl dipeptide esters are the 1-methyl-1’-N-{para-(ferrocenyl) benzoyl} glycine glycine ethyl ester with an IC50 value of 2.8 ± 1.23 µM, the 1-ethyl-1’–N-{para-(ferrocenyl) benzoyl} glycine glycine ethyl ester with an IC50 value of 3.5 ± 0.82 µM and the 1-methyl-1’-N-{meta-(ferrocenyl) benzoyl} glycine glycine ethyl ester with an IC50 of 2.6 ± 0.62 µM and these derivatives are more cytotoxic in vitro than the clinically employed anti-cancer drug carboplatin. In addition, these compounds display improved bioactivity in comparison to the corresponding most active benzoyl analogues which were the N-{meta-(ferrocenyl) benzoyl} glycine L-alanine ethyl ester and N-{para-(ferrocenyl) benzoyl} glycine L-alanine ethyl ester which displayed IC50 values of 4.0 µM and 6.6 µM respectively The biological evaluation of N-{para-(ferrocenyl) ethynyl benzoyl}, N-{6-(ferrocenyl) ethynyl-2-naphthoyl} and N-{5-(ferrocenyl) ethynyl-2-furanoyl} amino acid and dipeptide esters were also carried out in the H1299 non-small cell lung cancer (NSCLC) cells. The most active derivatives of the N-{para-(ferrocenyl) ethynyl benzoyl}, N-{6-(ferrocenyl) ethynyl-2-naphthoyl} and N-{5-(ferrocenyl) ethynyl-2-furanoyl} amino acid and dipeptide esters are the N-{para-(ferrocenyl) ethynyl benzoyl} glycine L-alanine ethyl ester with an IC50 value of 3.8 ± 1.92 µM and the N-{6-(ferrocenyl) ethynyl-2-naphthoyl} sarcosine L-alanine ethyl ester with an IC50 value of 3.2 ± 2.64 µM. These compounds are more active than carboplatin with an IC50 value of 10 ± 1.60 µM but are less effective than cisplatin with an IC50 value of 1.5 ± 0.10 µM which are clinically employed anti-cancer drugs. However, the presence of the ethynyl moiety had a negative effect of anti-proliferative effect compared to analogous compounds prepared previously lacking the ethynyl group. For example for N-{6-(ferrocenyl) ethynyl-2-naphthoyl} γ-aminobutyric acid ethyl ester the IC50 value is 7.2 ± 1.51 µM whereas for N-(6-ferrocenyl-2-naphthoyl) γ-aminobutyric acid ethyl ester the IC50 value was 0.62 ± 0.03 µM

Item Type:Thesis (PhD)
Date of Award:March 2013
Refereed:No
Supervisor(s):Kenny, Peter T.M.
Uncontrolled Keywords:Ferrocene; Bioorganometallic chemistry; Dipeptides; Cytotoxicity; Lung cancer
Subjects:Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:17742
Deposited On:05 Apr 2013 12:12 by Peter Kenny. Last Modified 24 Apr 2017 15:09

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