title: Diverging DOS strategy using an allene-containing tryptophan scaffold and a library design that maximizes biologically relevant chemical space while minimizing the number of compounds.
abstract: A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a microwave-assisted allenic [2 + 2] cycloaddition reaction. This same tryptophan-derived precursor afforded an indolylmethyldihydrocyclopentapyridinone 14 when subjected to a rhodium(I)-catalyzed cyclocarbonylation reaction and an indolylmethylpyrrolidinocyclopentenones 16 when reacted with molybdenum hexacarbonyl. Construction of allenic tetrahydro-β-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-β-carboline, followed by a microwave-assisted allenic [2 + 2] cycloaddition reaction, provided tetrahydrocyclobutaindoloquinolizinones 24 and the tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used as templates for the construction of a virtual library of 11 748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes. Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D) fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327,000 compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space defined by these compounds and will be synthesized and screened for biological activity.
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Painter
authors.forename: Lirong
authors.initials: L
authors.lastname: Wang
authors.forename: Supriyo
authors.initials: S
authors.lastname: Majumder
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
authors.forename: Kay M
authors.initials: KM
authors.lastname: Brummond
mesh_terms: D000466:Alkadienes / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003500:Cyclization; D015195:Drug Design; D015394:Molecular Structure; D054852:Small Molecule Libraries; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D000466:Alkadienes; D054852:Small Molecule Libraries; C025947:propadiene; D014364:Tryptophan