Journal Article
Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity
Liu, Y; Yin, Y; Zhang, Z; Li, CJ; Zhang, H; Zhang, D; Jiang, C; Nomie, K; Zhang, L; Wang, ML; Zhao, G
European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254
Elsevier Masson s.r.l.
Targeting of Akt has been validated as a well rationalized approach to cancer treatment, and represents a promising therapeutic strategy for aggressive hematologic malignancies. We describe herein an exploration of novel Akt inhibitors for cancer therapy through structural optimization of previously described 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives. Our studies yielded a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides capable of potent inhibition of Akt1. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 10h induced cell apoptosis and cell cycle arrest in G2/M phase, and significantly downregulated the phosphorylation of Akt downstream effectors GSK3β and S6 in Jeko-1 cells. © 2017 Elsevier Masson SAS
Akt; Anticancer; Docking; Mantle cell lymphoma; Piperidyl; Pyrrolopyrimidines; 1 (tert butoxycarbonyl) 4 (3,4 dichlorophenyl)piperidine 4 carboxylic acid; 1 (tert butoxycarbonyl) 4 (4 chlorophenyl)piperidine 4 carboxylic acid; 1 (tert butoxycarbonyl) 4 (4 methoxyphenyl)piperidine 4 carboxylic acid; 1 (tert butoxycarbonyl) 4 phenylpiperidine 4 carboxylic acid; 4 (3 bromophenyl) 1 (tert butoxycarbonyl)piperidine 4 carboxylic acid; 4 (4 bromophenyl) 1 (tert butoxycarbonyl)piperidine 4 carboxylic acid; 4 (piperazin 1 yl) 7h pyrrolo[2,3 d]pyrimidine derivative; 4 [2 (4 amino 1,2,5 oxadiazol 3 yl) 1 ethyl 7 (3 piperidinylmethoxy) 1h imidazo[4,5 c]pyridin 4 yl] 2 methyl 3 butyn 2 ol; 5 bromo 4 chloro 7h pyrrolo[2,3 d]pyrimidine; 5 dichloro 7h pyrrolo[2,3 d]pyrimidine; antineoplastic agent; glycogen synthase kinase 3beta; protein kinase B inhibitor; tert butyl 4 (3 bromophenyl) 4 cyanopiperidine 1 carboxylate; tert butyl 4 (4 bromophenyl) 4 cyanopiperidine 1 carboxylate; tert butyl 4 (4 chlorophenyl) 4 cyanopiperidine 1 carboxylate; tert butyl 4 (5 bromo 7h pyrrolo[2,3 d]pyrimidin 4 yl) piperazine 1 carboxylate; tert butyl 4 (5 chloro 7h pyrrolo[2,3 d]pyrimidin 4 yl) piperazine 1 carboxylate; tert butyl 4 (7h pyrrolo[2,3 d]pyrimidin 4 yl)piperazine 1 carboxylate; tert butyl 4 cyano 4 (3,4 dichlorophenyl)piperidine 1 carboxylate; tert butyl 4 cyano 4 (4 methoxyphenyl)piperidine 1 carboxylate; tert butyl 4 cyano 4 phenylpiperidine 1 carboxylate; tert butyl 4 [4 (tert butyl)phenyl] 4 cyanopiperidine 1 carboxylate; tert butyl bis(2 chloroethyl)carbamate; unclassified drug; unindexed drug; [4 (7h pyrrolo[2,3 d]pyrimidin 4 yl)piperazin 1 yl][4 (3,4 dichlorophenyl)piperidin 4 yl]methanone; [4 (7h pyrrolo[2,3 d]pyrimidin 4 yl)piperazin 1 yl][4 (4 (tert butyl)phenyl)piperidin 4 yl]methanone; [4 (7h pyrrolo[2,3 d]pyrimidin 4 yl)piperazin 1 yl][4 (4 bromophenyl)piperidin 4 yl]methanone; [4 (7h pyrrolo[2,3 d]pyrimidin 4 yl)piperazin 1 yl][4 (4 chlorophenyl)piperidin 4 yl]methanone; [4 (7h pyrrolo[2,3 d]pyrimidin 4 yl)piperazin 1 yl][4 (4 methoxyphenyl)piperidin 4 yl]methanone; antineoplastic agent; protein kinase B; protein kinase inhibitor; antiproliferative activity; apoptosis; Article; bromination; cancer therapy; carbon nuclear magnetic resonance; cell cycle arrest; cell cycle G2 phase; cell cycle M phase; chlorination; controlled study; down regulation; drug efficacy; drug structure; drug synthesis; enzyme activity; enzyme phosphorylation; human; human cell; in vitro study; mantle cell lymphoma; mantle cell lymphoma cell; proton nuclear magnetic resonance; thin layer chromatography; antagonists and inhibitors; cell cycle checkpoint; cell proliferation; chemical structure; chemistry; dose response; drug effects; drug screening; metabolism; phosphorylation; structure activity relation; synthesis; tumor cell line; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Structure-Activity Relationship