Synthesis and active oxygen generation by new emodin derivatives and their gonadotropin-releasing hormone conjugates.
In an attempt to develop efficient chemotherapeutic agents targeted at malignant cells that express receptors, we synthesized five new emodin derivatives and their gonadotropin-releasing hormone (GnRH) conjugates to be used as potential photoactive conjugates. Emodin was modified at its hydroxy groups and included different spacers for conjugation of the peptide. We used electron spin resonance (ESR) and spin trapping techniques to study the light-stimulated redox properties of the emodin derivatives and their GnRH conjugates. Upon irradiation, all new emodin derivatives and their conjugates stimulated the formation of singlet oxygen, that is, (1)O(2), and oxygen radicals, that is, O(2)(-)(*) and OH(*). However, substantial differences were found between the tested derivatives as to the efficacy of reactive oxygen species (ROS) production. Because of its superior ROS production properties, [d-Lys(6)(MeoEmo)]GnRH was selected as a leading conjugate. En-route to evaluate its targeting capacity, this potentially cytotoxic conjugate was tested in vitro to determine its hormonal activity and binding affinity to GnRH receptors.
Lev-Goldman
Vered
V
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Mester
Brenda
B
Ben-Aroya
Nurit
N
Koch
Yitzhak
Y
Weiner
Lev
L
Fridkin
Mati
M
D002851:Chromatography, High Pressure Liquid; D004578:Electron Spin Resonance Spectroscopy; D004642:Emodin / Q000737:chemistry*; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010100:Oxygen / Q000737:chemistry*; D011966:Receptors, LHRH / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D004642:Emodin; D010100:Oxygen