29906-67-0Relevant articles and documents
Design and development of novel series of indole-3-sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors
Singh, Priti,Choli, Abhishek,Swain, Baijayantimala,Angeli, Andrea,Sahoo, Santosh K.,Yaddanapudi, Venkata M.,Supuran, Claudiu T.,Arifuddin, Mohammed
, (2021/10/29)
Indole is a privileged moiety with a wide range of bioactivities, making it a popular scaffold in drug design and development studies as well as in synthetic chemistry. Here, novel urea derivatives of indole, containing sulfonamide at position-3 of indole
Scaffold repurposing of in-house small molecule candidates leads to discovery of first-in-class cdk-1/her-2 dual inhibitors: In vitro and in silico screening
Elkamhawy, Ahmed,Ammar, Usama M.,Paik, Sora,Abdellattif, Magda H.,Elsherbeny, Mohamed H.,Lee, Kyeong,Roh, Eun Joo
supporting information, (2021/09/08)
Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property.
Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo
Liu, Yi-Min,Tu, Huang-Ju,Wu, Chueh-Heng,Lai, Mei-Jung,Yu, Shu-Chieh,Chao, Min-Wu,Wu, Yi-Wen,Teng, Che-Ming,Pan, Shiow-Lin,Liou, Jing-Ping
, (2021/05/10)
A series of ring-opened dihydroxybenzamides have been designed and synthesized as heat shock protein 90 inhibitors. One of derivatives, compound 6b ((N-ethyl-2,4-dihydroxy-5-isopropyl-N-(pyridin-3-yl)benzamide)) demonstrated remarkable antiproliferative activity against in human KRAS mutant A549 and EGFR T790 M mutant H1975 lung cancer cell lines with GI50 values of 0.07 and 0.05 μM, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI50 = 0.09 μM), liver Hep3B (GI50 = 0.20 μM) and breast MDA-MB-231 (GI50 = 0.09 μM), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC50 of 110.18 nM in HSP90α inhibitory activity, slightly better than reference compound 1 (17-AAG, IC50 = 141.62 nM) and achieves the degradation of multiple HSP90 client proteins in a dose- and time-dependent manner and downstream signaling of Akt in a concentration- and time-dependent manner in the human A549 lung cancer cell line. In the Boyden chamber assay, compound 6b can efficiently inhibit the migration of A549 cells when compared to the reference compound 1. It also induce significant activity through the apoptotic pathway. Treatment with 6b showed no vision toxicity (IC50 > 10 μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 μM values of IC50 and has no effect in hERG test. In a bidirectional Caco-2 permeability assay, compound 6b was classified as a highly permeable compound which is not a substrate of efflux transporters. In a pharmacokinetic study in rats, 6b showed an F = 17.8% of oral bioavailability. The effect of metabolic stability of compound 6b in human hepatocytes showed a T1/2 of 67.59 min. Compound 6b (50 mg/kg, po, daily) exhibits antitumor activity with a 72% TGD (tumor growth delay) in human A549 lung xenograft. The combination of 6b and afatinib, orally administered, showed tumor growth suppression with 67.5% of TGI in lung H1975 xenograft model. Thus compound 6b is a lead compound for further development of potential agents to treat lung cancer.
