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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis
Journal of Medicinal Chemistry, Volume 54, No. 12, Year 2011
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Description
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.
Authors & Co-Authors
Magedov, Igor V.
United States, Socorro
New Mexico Institute of Mining and Technology
Frolova, Liliya V.
United States, Socorro
New Mexico Institute of Mining and Technology
Manpadi, Madhuri
United States, Socorro
New Mexico Institute of Mining and Technology
Bhoga, Umadevi
South Africa, Johannesburg
University of the Witwatersrand
Tang, Hong
United States, Socorro
New Mexico Institute of Mining and Technology
Evdokimov, Nikolai M.
United States, Socorro
New Mexico Institute of Mining and Technology
George, Olivia L.
United States, Las Cruces
New Mexico State University
Hadje-Georgiou, Kathy
South Africa, Johannesburg
University of the Witwatersrand
Renner, Steffen
Germany, Dortmund
Max-planck-institut Für Molekulare Physiologie
Getlik, Matthäus
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Kinnibrugh, Tiffany L.
United States, Socorro
New Mexico Institute of Mining and Technology
Fernandes, Manuel A.
South Africa, Johannesburg
University of the Witwatersrand
van Slambrouck, Séverine
United States, Socorro
New Mexico Institute of Mining and Technology
Steelant, Wim F.A.
United States, Socorro
New Mexico Institute of Mining and Technology
Shuster, Charles Bradley
United States, Las Cruces
New Mexico State University
Rogelj, Snežna
United States, Socorro
New Mexico Institute of Mining and Technology
van Otterlo, Willem A. L.
South Africa, Johannesburg
University of the Witwatersrand
South Africa, Stellenbosch
Stellenbosch University
Kornienko, Alexander V.
United States, Socorro
New Mexico Institute of Mining and Technology
Statistics
Citations: 57
Authors: 18
Affiliations: 6
Identifiers
Doi:
10.1021/jm200410r
ISSN:
00222623
e-ISSN:
15204804
Research Areas
Cancer
Study Design
Case-Control Study