Parallel solid-phase synthesis of 3β-peptido-3α-hydroxy-5α-androstan-17-one derivatives for inhibition of type 3 17β-hydroxysteroid dehydrogenase

• Published in: Bioorganic & medicinal chemistry 2001-12, Vol.9 (12), p.3101-3111
• Main Authors: Maltais, René, Luu-The, Van, Poirier, Donald
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; General aspects; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00182-1

Type 3 17β-hydroxysteroid dehydrogenase (17β-HSD), a key steroidogenic enzyme, transforms 4-androstene-3,17-dione (Δ 4-dione) into testosterone. In order to produce potential inhibitors, we performed solid-phase synthesis of model libraries of 3β-peptido-3α-hydroxy-5α-androstan-17-ones with 1, 2, or 3 levels of molecular diversity, obtaining good overall yields (23–58%) and a high average purity (86%, without any purification steps) using the Leznoff's acetal linker. The libraries were rapidly synthesized in a parallel format and the generated compounds were tested as inhibitors of type 3 17β-HSD. Potent inhibitors were identified from these model libraries, especially six members of the level 3 library having at least one phenyl group. One of them, the 3β-( N-heptanoyl- l-phenylalanine- l-leucine-aminomethyl)-3α-hydroxy-5α-androstan-17-one ( 42) inhibited the enzyme with an IC 50 value of 227 nM, which is twice as potent as the natural substrate Δ 4-dione when used itself as an inhibitor. Using the proliferation of androgen-sensitive (AR +) Shionogi cells as model of androgenicity, the compound 42 induced only a slight proliferation at 1 μM (less than previously reported type 3 17β-HSD inhibitors) and, interestingly, no proliferation at 0.1 μM. Three model libraries of 3β-ADT-derivatives were synthesized in good overall yields and high average purity (86%) using polymer-bound glycerol and a steroid precursor. Chemical synthesis and biological evaluation were reported.