Jójárt Rebeka, Pécsy Szabolcs, Keglevich György, Szécsi Mihály, Rigó Réka, Özvegy-Laczka Csilla, Kecskeméti Gábor, Mernyák Erzsébet
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary.
Beilstein J Org Chem. 2018 Nov 14;14:2838-2845. doi: 10.3762/bjoc.14.262. eCollection 2018.
Novel 2- or 4-phosphonated 13α-estrone derivatives were synthesized via the Hirao reaction. Bromo regioisomers (2- or 4-) of 13α-estrone and its 3-benzyl or 3-methyl ether were reacted with diethyl phosphite or diphenylphosphine oxide using Pd(PPh) as catalyst under microwave irradiation. The influence of the new compounds on the transport function of the organic anion transporting polypeptide OATP2B1 was investigated by measuring Cascade Blue uptake. Derivatives bearing a 3-benzyl ether function displayed substantial submicromolar OATP2B1 inhibitory activity. The inhibitory effects of the compounds on human placental steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated by in vitro radiosubstrate incubation methods. None of the test compounds inhibited the STS markedly. The structure-activity relationship evaluation revealed that 2-substituted 3-hydroxy derivatives are able to inhibit the 17β-HSD1 enzyme with submicromolar IC values. Dual OATP2B1 and 17β-HSD1 inhibitors have been identified.
通过平贺反应合成了新型的2-或4-膦酰化13α-雌酮衍生物。13α-雌酮及其3-苄基或3-甲基醚的溴代区域异构体（2-或4-）与亚磷酸二乙酯或二苯基氧化膦在微波辐射下以Pd(PPh)为催化剂进行反应。通过测量级联蓝摄取来研究新化合物对有机阴离子转运多肽OATP2B1转运功能的影响。带有3-苄基醚官能团的衍生物表现出显著的亚微摩尔级OATP2B1抑制活性。通过体外放射性底物孵育方法研究了这些化合物对人胎盘类固醇硫酸酯酶（STS）和1型17β-羟基类固醇脱氢酶同工酶（17β-HSD1）的抑制作用。所测试的化合物均未明显抑制STS。构效关系评估表明，2-取代的3-羟基衍生物能够以亚微摩尔IC值抑制17β-HSD1酶。已鉴定出双OATP2B1和17β-HSD1抑制剂。
