Probing chemical space with alkaloid-inspired libraries.
Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp(3)-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp(3) content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
Michael C
MC
McLeod
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
Gurpreet
G
Singh
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
James N
JN
Plampin
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
Digamber
D
Rane
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
Jenna L
JL
Wang
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
Victor W
VW
Day
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
Jeffrey
J
Aubé
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry*; D047151:Amaryllidaceae Alkaloids / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry; D061565:Cycloaddition Reaction; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*
D000470:Alkaloids; D047151:Amaryllidaceae Alkaloids; D001688:Biological Products; D054852:Small Molecule Libraries; C431548:lepadiformine