本人為了尋找甲硫胺酸腺甘基轉移酵素（Methionine S-adenosyltransferase；MAT）新抑制劑與維他命A酸對HL-60人類血癌細胞誘導分化之加強劑，設計合成一系列HP類緣化合物（HP1~12）。標的化合物之合成係採用solid phase peptide synthesis 之方法而製備的。接著再根據表面薄層電漿共振技術 (SPR) 之原理設計出對於HL-60人類血癌細胞內之MAT酵素的活性抑制測試；其結果顯示出天然的HP類緣化合物PyroGlu-Glu-Glu-Cys-Lys-OH (HP1)及PyroGlu-Asp-Asp-Cys-Lys-OH (HP3)皆表現出最大的抑制活性。進一步，將HP1上的C-端-COOH集團改為-CONH2集團時，其抑制活性更甚於HP1。 經測試一系列HP類緣化合物對於HL-60人類血癌細胞所產生促進分化及抑制增殖能力的活性之後，建立了初步的結構與活性關係。同時發現所有的HP類緣化合物 (HP1~12)都具有明顯的活性，其中以PaA-Glu-Glu- Cys-Lys-NH2 (HP12)活性最強且其促進維他命A酸誘導細胞活化能力相當於苯醋酸的50倍。; In my search for novel inhibitors of methionine S-adenosyl transferase（MAT）and potentiators of the activity of retinoic acid in inducing differentiation of HL-60 cells. A series of HP analogues（HP1~12）were designed. The solid phase peptide synthetic procedure was adopted for the preparation of these target peptides. Preliminary tests of their inhibitory effects on the MAT of HL-60 cells was performed according to the surface plasmon resonance（SPR）technology. Results indicate that PyroGlu-Glu-Glu-Cys-Lys-OH (HP1) and PyroGlu-Asp-Asp-Cys-Lys-OH(HP3) ,both being natural HP, displayed significant inhibitory effects. The synthetic HP6, obtained by converting the C-terminal-COOH of HP1 to-CONH2, demonstrated improved activity over HP1. After testing the target peptides on HL-60 cells for differentiation and proliferation capability, a preliminary SAR was established. All of the peptides (HP1~12) showed significant activity. Among them, PaA-Glu-Glu-Cys-Lys-NH2 (HP12) exhibited the highest activity with about 50 times the potency of phenylacetic acid in the potentiating activity of retinoic acid to induce cell differentiation.
