DIRECT ANTIPROLIFERATIVE EFFECT ON BREAST CANCER CELLS OF NEW LEUPROLIDE ANALOGUES WITH MODIFICATIONS IN POSITIONS 3 6

摘要

Analogues of GnRH have been widely used in oncology and gynaecology to induce reversible chemical castration. In addition to the classic hypophysiotropic action of GnRH, it has been shown that many malignant cells, such as breast cancer cells, secrete GnRH and express the GnRH receptor/s. Leuprolide is a synthetic GnRH agonist and active pharmaceutical ingredient of commercially available drugs. In order to study the effect of modifications in positions 3 and 6 of leuprolide on breast cancer cell proliferation, we synthesized fifteen new conformationally restricted analogues. D-Leu~6 of Leuprolide was substituted by α,α dialkyl amino acids (Aib: α-aminoisobutyric acid, Deg: diethylglycine), D-Gly(tBu) and β-cycloexyl-D-alanine (D-Cha) and/or Trp~3 by D-Trp, d- and L-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid (Tic) (Table 1).