Design and synthesis of novel furoquinoline based inhibitors of multiple targets in the PI3K/Akt-mTOR pathway.
We herein report the design and synthesis of furoquinoline based novel molecules (16-36) and their in vitro multiple targeted inhibitory potency against PI3K/Akt phosphorylation and mTOR using cell based and cell-free kinase assay. In particular, compound 23 in addition to PI3K-mTOR inhibitory potency, it has shown potent inhibition of hypoxia-induced accumulation of HIF-1alpha protein in U251-HRE cell line. The inhibitory activities of compound 23 were confirmed by Western blot analysis, using human non-small cell lung carcinoma H-460 cell line and glioblastoma U251 cell lines.
Lohar
Manoj V
MV
Department of Medicinal Chemistry, Nicholas Piramal Research Centre, Goregaon (East), Mumbai 400 063, India.
Mundada
Ramswaroop
R
Bhonde
Mandar
M
Padgaonkar
Amol
A
Deore
Vijaykumar
V
Yewalkar
Nilambari
N
Bhatia
Dimple
D
Rathos
Maggie
M
Joshi
Kalpana
K
Vishwakarma
Ram A
RA
Kumar
Sanjay
S
D015153:Blotting, Western; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
D004791:Enzyme Inhibitors; D005663:Furans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C530873:7-methoxy-4-(4-nitrophenylthio)furo(2,3-b)quinoline; C546842:MTOR protein, human