Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl.
Imatinib (STI571) is the frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML). However, resistance to imatinib due to point mutations in Bcr-Abl kinase domain is an emerging problem. We recently reported that triptolide (compound 1) could effectively kill CML cells including those harboring T315I mutant Bcr-Abl. In the present study, we designed a series of C-14 triptolide derivatives with C-14-hydroxyl substituted by different amine esters (3-18): 3-6 and 13 (by aliphatic chain amine esters); 7-9, 11, 12 and 15-18 (by alicyclic amine esters with different size), and 10 and 14 (by aralkylamine esters).The compounds were examined for their antineoplastic activity against CML cells (including KBM5-T315I cells) in terms of proliferation inhibition, apoptosis and signal transduction. Nude mouse xenograft model was also used to evaluate the in vivo activity. Compounds 2-9, 11-14, 17 and 18 exhibited a potent inhibitory activity against KBM5 and KBM5-T315I cells. This series of derivatives down-regulated Bcr-Abl mRNA. Compounds 4, 5, 8 and 9 were further examined for their impact on signaling and apoptosis with immunoblotting. Compound 5 was chosen for evaluation in a nude mouse xenograft model. The stereo-hindrance of C-14 group appeared to be responsible for the antitumor effect. The computational small molecule-protein docking analysis illustrated the possible interaction between compound 9 and RNA polymerase II. Our results suggest that this series of derivatives may be promising agents to overcome imatinib-resistance caused by the Bcr-Abl-T315I mutation.
Xu
Fang
F
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xingangxi Road, Guangzhou 510275, People's Republic of China.
Shi
Xianping
X
Li
Shichang
S
Cui
Jieshun
J
Lu
Zhongzheng
Z
Jin
Yanli
Y
Lin
Yongcheng
Y
Pang
Jiyan
J
Pan
Jingxuan
J
D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D015536:Down-Regulation; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014867:Water / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D014867:Water; C001899:triptolide; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl