Abadi Ashraf H, Lehmann Jochen, Piazza Gary A, Abdel-Halim Mohammad, Ali Mohamed S M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry, Friedrich-Schiller University, Philosophenweg 14, 07743 Jena, Germany.
Int J Med Chem. 2011;2011:562421. doi: 10.1155/2011/562421. Epub 2011 Feb 23.
Two series of fused tetrahydro-β-carboline hydantoin and tetrahydro-β-carboline thiohydantoin derivatives with a pendant 2,4-dimethoxyphenyl at position 5 were synthesized, and chiral carbons at positions 5 and 11a swing from R,R to R,S, S,R, and S,S. The prepared analogues were evaluated for their capacity to inhibit phosphodiesterase 5 (PDE5) isozyme. The R absolute configuration of C-5 in the β-carboline hydantoin derivatives was found to be essential for the PDE5 inhibition. Chiral carbon derived from amino acid even if of the S configuration (L-tryptophan) may lead to equiactive or more active isomers than those derived from amino acid with the R configuration (D-tryptophan). This expands the horizon from which efficient PDE5 inhibitors can be derived and may offer an economic advantage. The thiohydantoin derivatives were less active than their hydantoin congeners.
合成了两个系列在5位带有2,4 - 二甲氧基苯基侧链的稠合四氢-β-咔啉乙内酰脲和四氢-β-咔啉硫代乙内酰脲衍生物，5位和11a位的手性碳从R,R构型转变为R,S、S,R和S,S构型。对所制备的类似物进行了抑制磷酸二酯酶5（PDE5）同工酶能力的评估。发现β-咔啉乙内酰脲衍生物中C-5的R绝对构型对于PDE5抑制至关重要。即使是S构型（L-色氨酸）的氨基酸衍生的手性碳，也可能产生与R构型（D-色氨酸）的氨基酸衍生的异构体同等活性或活性更高的异构体。这拓宽了可从中获得有效PDE5抑制剂的视野，并且可能具有经济优势。硫代乙内酰脲衍生物的活性低于其乙内酰脲同类物。
