2. Academic Validation
  3. Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis

Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis

  • J Med Chem. 2011 Jun 23;54(12):4234-46. doi: 10.1021/jm200410r.
Igor V Magedov 1,  Liliya Frolova,  Madhuri Manpadi,  Uma devi Bhoga,  Hong Tang,  Nikolai M Evdokimov,  Olivia George,  Kathy Hadje Georgiou,  Steffen Renner,  Matthäus Getlik,  Tiffany L Kinnibrugh,  Manuel A Fernandes,  Severine Van slambrouck,  Wim F A Steelant,  Charles B Shuster,  Snezna Rogelj,  Willem A L van Otterlo,  Alexander Kornienko
Affiliations

Affiliation

  • 1 Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, United States. imagedov@nmt.edu
PMID: 21615090 DOI: 10.1021/jm200410r
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.

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