title: Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis.
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.
authors: Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, United States. imagedov@nmt.edu
authors: Igor V
authors: IV
authors: Magedov
authors: Liliya
authors: L
authors: Frolova
authors: Madhuri
authors: M
authors: Manpadi
authors: Uma devi
authors: Ud
authors: Bhoga
authors: Hong
authors: H
authors: Tang
authors: Nikolai M
authors: NM
authors: Evdokimov
authors: Olivia
authors: O
authors: George
authors: Kathy Hadje
authors: KH
authors: Georgiou
authors: Steffen
authors: S
authors: Renner
authors: Matthäus
authors: M
authors: Getlik
authors: Tiffany L
authors: TL
authors: Kinnibrugh
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authors: Fernandes
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authors: Van slambrouck
authors: Wim F A
authors: WF
authors: Steelant
authors: Charles B
authors: CB
authors: Shuster
authors: Snezna
authors: S
authors: Rogelj
authors: Willem A L
authors: WA
authors: van Otterlo
authors: Alexander
authors: A
authors: Kornienko
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