Estrogen-derived steroidal metal complexes: agents for cellular delivery of metal centers to estrogen receptor-positive cells.
Targeted cellular delivery of drugs to specific tissues is an important goal in biomedical chemistry. Achieving this requires harnessing and applying molecular-level recognition events prevalent in (or specific to) the desired tissue type. Tissues rich in estrogen receptors (ERs), which include many types of breast cancer, accumulate molecules that have high binding affinities for these receptors. Therefore, molecules that (i) bind to the ER, (ii) have favorable cellular transport properties, and (iii) contain a second functionality (such as a center that may be used for diagnostic imaging or medical therapy) are exciting synthetic targets in the field of drug delivery. To this end, we have prepared a range of metallo-estrogens based on 17alpha-ethynylestradiol and examined their binding to the ER both as isolated receptor and in whole cell assays (ER positive MCF-7 cells). Estrogens functionalized with metal binding units are prepared by palladium-catalyzed cross-coupling reactions and a wide range of metal centers introduced readily. All the compounds prepared and tested exhibit effective binding to the estrogen receptor and are delivered across the cell membrane into MCF-7 cells. In the whole cell assays, despite their monocationic nature, the palladium and platinum complexes prepared exhibit similar (and even enhanced) receptor binding affinities compared to their corresponding neutral free ligands. It is unprecedented for a higher ER binding affinity to be observed for a cationic complex than for its metal-free ligand.
Jackson
A
A
Department of Chemistry, University of Warwick, Coventry CV4 7AL U.K.
Davis
J
J
Pither
R J
RJ
Rodger
A
A
Hannon
M J
MJ
D001692:Biological Transport; D001943:Breast Neoplasms / Q000378:metabolism; D002384:Catalysis; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D009942:Organometallic Compounds; D011725:Pyridines; D011960:Receptors, Estrogen; D004997:Ethinyl Estradiol; D010984:Platinum; D012211:Rhenium; D004121:Dimethyl Sulfoxide