Synthesis and biological evaluation of phorboxazole congeners leading to the discovery and preparative-scale synthesis of (+)-chlorophorboxazole a possessing picomolar human solid tumor cell growth inhibitory activity.
Highly convergent syntheses of eight phorboxazole congeners and their evaluation against a diverse panel of human solid tumor cancer cell lines have been achieved. Specifically, the C(45-46) alkyne, alkene, and alkane phorboxazole A analogues [(+)-4-(+)-6] were constructed and found to display single digit nanomolar cell growth inhibitory activities in a series of human cancer cell lines. The structurally simplified C(11-15)-acetal congener (+)-20Z also proved potent albeit reduced (cf. 34.6 nM) when evaluated against the same cell line panel. Importantly, (+)-C(46)-chlorophorboxazole A (3) displayed picomolar (pM) inhibitory activity in several cell lines.
Smith
Amos B
AB
Department of Chemistry, The Penn Center for Molecular Discovery, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. smithab@sas.upenn.edu
Razler
Thomas M
TM
Meis
Regina M
RM
Pettit
George R
GR
D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D006576:Heterocyclic Compounds, 4 or More Rings; D010080:Oxazoles; C408887:phorboxazole A