Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis
Date
2011
Authors
Magedov I.V.
Frolova L.
Manpadi M.
Bhoga U.D.
Tang H.
Evdokimov N.M.
George O.
Hadje Georgiou K.
Renner S.
Getlik M.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings. © 2011 American Chemical Society.
Description
Keywords
2 hydroxy 7 (3,4,5 trimethoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 4 (2 hydroxy 3 methoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (3 bromo 4,5 dimethoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (3 bromophenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (3,4,5 trimethoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (3,5 dibromo 2 hydroxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (3,5 dibromophenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (3,5 dibromophenyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (4 bromo 2 thienyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (5 bromo 2 hydroxy 3 methoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (5 bromo 2 hydroxy 3 methoxyphenyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (5 bromo 2 hydroxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (5 bromo 2 hydroxyphenyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (5 bromo 3 pyridinyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 4 (5 bromo 3 pyridinyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one, 7 (3 bromo 4,5 dimethoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 7 (3,4,5 trimethoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 7 (3,5 dibromo 2 hydroxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 7 (3,5 dibromophenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 7 (4 bromo 2 thienyl) 7,11 dihydrobenzo[h]furo[3,4 b] quinolin 8(10h) one, 7 (5 bromo 2 hydroxy 3 methoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 7 (5 bromo 2 hydroxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, 7 (5 bromo 3 pyridinyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one, antineoplastic agent, beta tubulin, dihydropyridopyrazole derivative, heterocyclic compound, podophyllotoxin, tubulin, unclassified drug, unindexed drug, antineoplastic activity, apoptosis, article, cell proliferation, drug binding site, drug synthesis, human, human cell, in vitro study, molecular docking, molecular model, polymerization, Antineoplastic Agents, Apoptosis, Binding Sites, Computer Simulation, Hela Cells, Heterocyclic Compounds, Humans, Indoles, Models, Molecular, Molecular Mimicry, Naphthalenes, Podophyllotoxin, Pyrazoles, Pyridines, Small Molecule Libraries, Stereoisomerism, Tubulin Modulators
Citation
Journal of Medicinal Chemistry
54
12
http://www.scopus.com/inward/record.url?eid=2-s2.0-79959480967&partnerID=40&md5=d9614c808abbad0880eaba5fd373337e
54
12
http://www.scopus.com/inward/record.url?eid=2-s2.0-79959480967&partnerID=40&md5=d9614c808abbad0880eaba5fd373337e