title: Synthesis of natural-like acylphloroglucinols with anti-proliferative, anti-oxidative and tube-formation inhibitory activity.
abstract: Two series of natural and natural-like mono- and bicyclic acylphloroglucinols derived from secondary metabolites in the genus Hypericum (Hypericaceae) were synthesised and tested in vitro for anti-proliferative and tube-formation inhibitory activity in human microvascular endothelial cells (HMEC-1). In addition, their anti-oxidative activity was determined via an ORAC-assay. The first series of compounds (4a-e) consisted of geranylated monocyclic acylphloroglucinols with varying aliphatic acyl substitution patterns, which were subsequently cyclised to the corresponding 2-methyl-2-prenylchromane derivatives (5a and 5d). The second series involved compounds containing a 2,2-dimethylchromane skeleton with differing aromatic acyl substitution (6a-d and 7a-e). Compound 7a, (5,7-dihydroxy-2,2-dimethylchroman-6-yl)-(3,4-dihydroxyphenyl)methanone), showed the highest in vitro anti-proliferative activity with an IC50 of 0.88 ± 0.08 μM and a remarkable anti-oxidative activity of 2.8 ± 0.1 TE from the ORAC test. Interestingly, the high anti-proliferative activity of these acylphloroglucinols was not associated with tube-formation inhibition. Compounds (E)-1-(3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4,6-trihydroxyphenyl)-2-methylbutan-1-one (4d) and (5,7-dihydroxy-2,2-dimethylchroman-6-yl)(3,4-dimethoxyphenyl)methanone (6a) exhibited moderate to weak anti-proliferative effects (IC50 11.0 ± 1 μM and 48.0 ± 4.3 μM, respectively) and inhibited the capillary-like tube formation of HMEC-1 in vitro, whereas 7a was inactive. The most active compound in the ORAC assay was 7c, which exhibited an anti-oxidative effect of 6.6 ± 1.0 TE. However, this compound showed only weak activity during the proliferation assay (IC50 53.8 ± 0.3) and did not inhibit tube-formation.
authors.affiliation: Universität Regensburg, Institute of Organic Chemistry, Universitätsstr. 31, D-93053 Regensburg, Germany.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Universität Regensburg, Pharmaceutical Biology, Universitätsstr. 31, D-93053 Regensburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Universität Regensburg, Pharmaceutical Biology, Universitätsstr. 31, D-93053 Regensburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Tremmel
authors.affiliation: Universität Regensburg, Pharmaceutical Biology, Universitätsstr. 31, D-93053 Regensburg, Germany. Electronic address: joerg.heilmann@chemie.uni-regensburg.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Universität Regensburg, Institute of Organic Chemistry, Universitätsstr. 31, D-93053 Regensburg, Germany. Electronic address: burkhard.koenig@chemie.uni-regensburg.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D010696:Phloroglucinol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D010696:Phloroglucinol
keywords: Acylphloroglucinol; Anti-proliferative activity; Chromane; HMEC-1; ORAC; Tube formation