Role of aromatic substituents on the antiproliferative effects of diphenyl ferrocenyl butene compounds.
We have been exploring the cytotoxic effects of conjugated phenylferrocene systems on breast cancer cells. Complexes with p-OH, p-NH(2), and p-NHC(O)CH(3) substitution show particularly high activity, with IC(50) values in the low or sub micromolar range for both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines. We now present the synthesis, X-ray crystal structures and biochemical studies of analogous halogen or pseudo-halogen para-substituted compounds with R = Cl, (Z)-7a; Br, (Z)-7b; CF(3), (E)-7c; and CN, (E)-7d and (Z)-7d. Lacking hydrogen bonding groups, the compounds have low, but non-zero, relative binding affinity values for the oestrogen receptor alpha (RBA <or= 0.55%) as well as mildly exothermic ligand binding in in silico ER docking experiments. All compounds show estrogenic (proliferative) activity on the MCF-7 cell line. On MDA-MB-231 cells, the cyano complex (Z)-7d shows a reasonable cytotoxic effect (IC(50) = 11 microM), its isomer (E)-7d is only slightly cytotoxic (IC(50) = 60 microM), while the Cl, Br, and CF(3) derivatives have no effect. Cytotoxic properties, while they correlate somewhat with the resonance donating abilities of the substituent, are more strongly dependent on the presence of a proton in the functional group, supporting our prior proposition that electrophilic quinoid forms of the compounds could be active species in the cell. A correlation of the redox potential of the ferrocenyl moiety with the Hammett-Taft constants of the substituents was observed.
Zekri
Ouardia
O
Laboratoire Charles Friedel, UMR CNRS 7223, Ecole Nationale Supérieure de Chimie de Paris, Paris, France.
Hillard
Elizabeth A
EA
Top
Siden
S
Vessières
Anne
A
Pigeon
Pascal
P
Plamont
Marie-Aude
MA
Huché
Michel
M
Boutamine
Sultana
S
McGlinchey
Michael J
MJ
Müller-Bunz
Helge
H
Jaouen
Gérard
G
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D002073:Butanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012756:Sheep; D013329:Structure-Activity Relationship; D014599:Uterus / Q000737:chemistry
D018931:Antineoplastic Agents, Hormonal; D002073:Butanes; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005296:Ferrous Compounds; C543442:diphenyl ferrocenyl butene