title: Design and Synthesis of a Screening Library Using the Natural Product Scaffold 3-Chloro-4-hydroxyphenylacetic Acid.
abstract: The fungal metabolite 3-chloro-4-hydroxyphenylacetic acid (1) was utilized in the generation of a unique drug-like screening library using parallel solution-phase synthesis. A 20-membered amide library (3-22) was generated by first converting 1 to methyl (3-chloro-4-hydroxyphenyl)acetate (2), then reacting this scaffold with a diverse series of primary amines via a solvent-free aminolysis procedure. The structures of the synthetic analogues (3-22) were elucidated by spectroscopic data analysis. The structures of compounds 8, 12, and 22 were confirmed by single X-ray crystallographic analysis. All compounds were evaluated for cytotoxicity against a human prostate cancer cell line (LNCaP) and for antiparasitic activity toward Trypanosoma brucei brucei and Plasmodium falciparum and showed no significant activity at 10 μM. The library was also tested for effects on the lipid content of LNCaP and PC-3 prostate cancer cells, and it was demonstrated that the fluorobenzyl analogues (12-14) significantly reduced cellular phospholipid and neutral lipid levels.
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
authors: Rohitesh
authors: R
authors: Kumar
authors: ‡Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4102, Australia.
authors: Martin C
authors: MC
authors: Sadowski
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.|‡Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4102, Australia.
authors: Claire
authors: C
authors: Levrier
authors: ‡Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4102, Australia.
authors: Colleen C
authors: CC
authors: Nelson
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
authors: Amy J
authors: AJ
authors: Jones
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
authors: John P
authors: JP
authors: Holleran
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
authors: Vicky M
authors: VM
authors: Avery
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
authors: Peter C
authors: PC
authors: Healy
authors: †Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
authors: Rohan A
authors: RA
authors: Davis
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D000962:Antimalarials; D001688:Biological Products; D010648:Phenylacetates; C029718:3-chloro-4-hydroxyphenylacetic acid