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D-Phe-Pro-Arg-H sulfate (GYKI-14166) is a highly active and selective inhibitor of thrombin both in vitro and in vivo. Recent studies on the stability of D-Phe-Pro-Arg-H in neutral aqueous solution at higher temperature have revealed that it is transformed into inactive 5,6,8,9,10,10a-hexahydro-2-(3'- guanidinopropyl)-5-benzyl-6-oxo- imidazo[1,2-a]pyrrolo[2,1-c]pyrazine. No such inactivation could be observed with Boc-D-Phe-Pro-Arg-H (GYKI-14451), but this compound was far less specific than the free peptide as it inhibited thrombin and, for instance, plasmin equally well. Assuming that the transformation of free tripeptide aldehyde, mentioned above, can only be initiated by a primary amino terminus, the N-alkyl derivatives of D-Phe-Pro-Arg-H were prepared. Of the new analogues, D-MePhe-Pro-Arg-H (GYKI-14766) proved to be as highly active and selective anticoagulant as its parent compound and was not inactivated by transformation into a heterocyclic compound.

According to our results, ionic imbalance and dialysis itself may cause changes in P duration and dispersion simultaneously.

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 derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine' and D-ornithine6 or N8-(2,3-diaminopropionyl)-D-lysine and N8-(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 afnities of peptides containing two cytotoxic side chains were lower. Chemotherapy has been, for many decades, one of the main approaches for the treatment of malignant neoplasms. Despite the development of modem, more specific cytotoxic drugs, their nonselective action on cells other than cancerous ones remains a major problem. A recent modality for the treatment of hormone-sensitive tumors is based on the use of agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH) (1). Some LH-RH agonists substituted in position 6, 10, or both are much more active than LH-RH and also possess prolonged activity (1-3). Changes in positions 1, 2, 3, and 6 and occasionally in positions 5 and 10 of the LH-RH molecule lead to the formation of powerful antagonists (1-4), which inhibit the release of LH and folliclestimulating hormone from the pituitary, create a state of sex-steroid deprivation, and thus have potential therapeutic applications in the treatment of some hormone-dependent cancers such as those of prostate and breast (1, 5).Ideal anticancer drugs would theoretically be those that eradicate cancer cells without harming normal cells. Some hormonal peptide analogues carrying antineoplastic agents could be used for endocrine therapy and at the same time for targeted chemotherapy of cancers that possess receptors for their peptide moieties on tumor cell membranes.

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