从易于获得的起始原料中,以5-6个步骤合成了许多5-arylisatin衍生物。它们的结构通过1 H NMR和13 C NMR以及LC / MS确认。在体外通过MTT分析评估了这些新颖的靛红对人白血病K562细胞的细胞毒性。SAR研究表明,N-取代的苄基和C-5取代的苯基基团大大增强了它们的细胞毒性活性,而保持在母体环上C-3上完整的羰基官能度是必需的。尤其是,N-(对甲氧基苄基)-5-(对甲氧基苯基)Isatin(化合物2m)对K562细胞系表现出最高的抗肿瘤活性(IC50 = 0.03μM)。此外,化合物2m的治疗可显着抑制肝癌HepG2细胞的增殖和迁移,这也可以减少人脐静脉内皮细胞(HUVEC)管的形成。总之,化合物2m在体外通过血管生成反应表现出非常良好的癌细胞增殖抑制作用,并且2m可能是有希望的用于癌症治疗的血管生成抑制剂。
Fragment-Based Discovery of 5-Arylisatin-Based Inhibitors of Matrix Metalloproteinases 2 and 13
作者:Mariangela Agamennone、Dmitry S. Belov、Antonio Laghezza、Vladimir N. Ivanov、Anton M. Novoselov、Ivan A. Andreev、Nina K. Ratmanova、Andrea Altieri、Paolo Tortorella、Alexander V. Kurkin
DOI:10.1002/cmdc.201600266
日期:2016.9.6
Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound
Identification of the First Highly Subtype-Selective Inhibitor of Human GABA Transporter GAT3
作者:Maria Damgaard、Anas Al-Khawaja、Stine B. Vogensen、Andreas Jurik、Maarten Sijm、Maria E. K. Lie、Mathias I. Bæk、Emil Rosenthal、Anders A. Jensen、Gerhard F. Ecker、Bente Frølund、Petrine Wellendorph、Rasmus P. Clausen
DOI:10.1021/acschemneuro.5b00150
日期:2015.9.16
Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [H-3]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure activity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC50 values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) revealed a noncompetitive mode of inhibition at hGAT3. This suggests that this compound class, which has no structural resemblance to GABA, has a binding site different from the substrate, GABA. This was supported by a molecular modeling study that suggested a unique binding site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes.