Highly Potent Metallopeptide Analogues of Luteinizing Hormone-Releasing Hormone

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 86; no. 16; pp. 6313 - 6317
• Main Authors: Bajusz, S., Janaky, T., Csernus, V. J., Bokser, L., Fekete, M., Srkalovic, G., Redding, T. W., Schally, A. V.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.08.1989; National Acad Sciences
• Subjects: 550201 - Biochemistry- Tracer Techniques; Agonists; Amino Acid Sequence; AMINO ACIDS; ANIMAL CELLS; Animals; Antineoplastic agents; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; Biological and medical sciences; BODY; Breast cancer; Breast Neoplasms - metabolism; CARBOXYLIC ACIDS; Cell growth; Cell Membrane - metabolism; Cell membranes; CHEMICAL REACTIONS; CHROMATOGRAPHY; Chromatography, High Pressure Liquid; Cisplatin - analogs & derivatives; Cisplatin - chemical synthesis; Cisplatin - pharmacology; Copper - pharmacology; CROSS-LINKING; DAYS LIVING RADIOISOTOPES; Diamino amino acids; Dipeptides - chemical synthesis; ELECTRON CAPTURE RADIOISOTOPES; Female; General aspects; GLANDS; Gonadotropin-Releasing Hormone - analogs & derivatives; Gonadotropin-Releasing Hormone - chemical synthesis; Gonadotropin-Releasing Hormone - metabolism; Gonadotropin-Releasing Hormone - pharmacology; GONADOTROPINS; HORMONES; Humans; In Vitro Techniques; INTERMEDIATE MASS NUCLEI; IODINE 125; IODINE ISOTOPES; ISOTOPES; LH; LIBERINS; LIQUID COLUMN CHROMATOGRAPHY; Luteinization; Luteinizing Hormone - metabolism; LYSINE; MAMMARY GLANDS; Medical sciences; MEMBRANE PROTEINS; METALLOPROTEINS; Molecular Sequence Data; MOLECULAR STRUCTURE; Nickel; NUCLEI; ODD-EVEN NUCLEI; ORGANIC ACIDS; ORGANIC COMPOUNDS; Organometallic Compounds - chemical synthesis; Organometallic Compounds - pharmacology; ORGANS; Ovulation - drug effects; PEPTIDE HORMONES; Pharmacology. Drug treatments; Pituitary Gland - drug effects; Pituitary Gland - metabolism; PITUITARY HORMONES; PLATINUM COMPOUNDS; POLYMERIZATION; PROTEINS; RADIOISOTOPES; Rats; RECEPTORS; Receptors, LHRH - metabolism; SEPARATION PROCESSES; Structure-Activity Relationship; TRANSITION ELEMENT COMPOUNDS; Tumor cell line; TUMOR CELLS; Tumors; Antineoplastic agent; Human; Hypothalamic hormone; Analog; Animal; Gonadotropin RH; Affinity; Drug targeting; Tumor cell; Metal Complexes; Platinum II Complexes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.86.16.6313

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and trans-bis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N-ε(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1, D-Phe(pCl)2,D-Pal(3)2, Arg5, D-Lys{Dl-A2pr(Sal2Cu)}$^{6}$ , D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(Dl-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 μ g in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.