Analogues of luteinizing hormone-releasing hormone containing

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone deriva- tives (2-(hydroxymethyl)anthraquinone and the anticancer an- tibiotic doxorubicin), and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or Nt-(2,3-diaminopropionyl)- D-lysine and N6-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers (Ac-D-Nal(2)1,D-Phe(4Cl)2,D- Trp3,Arg5,D-Lys6,D-Ala10ILH-RH (where Nal(2) is 3-(2- naphthyl)alanine), (Ac-D-Nal(2)',D-Phe(4Cl)2,D-TrpArg5,- (2,3-diaminopropionyl)-D-Lys6,D-Alal')LH-RH, and their D-Pal(3)3 homologs (Pal(3) is 3-(3-pyridyl)alanine) as well as (AC-D-Nal(2) ,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,Ne-(2,3-diamino-