ABSTRACT
Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO inhibitors for both understanding the role of specific lipoxygenases in the cell and developing pharmaceutical therapeutics. To this end, we have modified a known lipoxygenase assay for high-throughput (HTP) screening of both the National Cancer Institute (NCI) and the UC Santa Cruz marine extract library (UCSC-MEL) in search of platelet-type 12-hLO (12-hLO) selective inhibitors. The HTP screen led to the characterization of five novel 12-hLO inhibitors from the NCI repository. One is the potent but non-selective michellamine B, a natural product, anti-viral agent. The other four compounds were selective inhibitors against 12-hLO, with three being synthetic compounds and one being alpha-mangostin, a natural product, caspase-3 pathway inhibitor. In addition, a selective inhibitor was isolated from the UCSC-MEL (neodysidenin), which has a unique chemical scaffold for a hLO inhibitor. Due to the unique structure of neodysidenin, steady-state inhibition kinetics were performed and its mode of inhibition against 12-hLO was determined to be competitive (K(i)=17microM) and selective over reticulocyte 15-hLO-1 (K(i) 15-hLO-1/12-hLO>30).
Subject(s)
Blood Platelets/enzymology , Databases, Factual , Drug Evaluation, Preclinical/methods , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/pharmacology , Combinatorial Chemistry Techniques , Drug Evaluation, Preclinical/statistics & numerical data , Humans , Isoenzymes/antagonists & inhibitors , Kinetics , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Molecular Structure , Reproducibility of Results , Structure-Activity RelationshipABSTRACT
Two new phakellin alkaloids, (-)-7-N-methyldibromophakellin (14) and (-)-7-N-methylmonobromophakellin (15), were isolated from an Agelas sp. sponge, collected near Wewak, Papua New Guinea. Inhibition assays employing both 12- and 15-human lipoxygenase isozymes (12-HLO, 15-HLO) were used to guide the isolation of 14, and LCMS data pointed the way to uncovering 15. The structure elucidations were completed by spectroscopic data analysis and comparisons to the properties of known phakellins. The lipoxygenase IC50 data showed that 14 was modest in its selective inhibition of 12-HLO. The phakellin family is uniquely marine-derived, and comments are offered on the biogenetic insights provided by these new structures.
Subject(s)
Alkaloids/isolation & purification , Enzyme Inhibitors/isolation & purification , Lipoxygenase Inhibitors , Piperazines/chemistry , Piperazines/isolation & purification , Porifera/chemistry , Pyrroles/chemistry , Pyrroles/isolation & purification , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guanidines/chemistry , Inhibitory Concentration 50 , Molecular Structure , Papua New Guinea , Piperazines/pharmacology , Pyrroles/pharmacology , Spiro Compounds/chemistryABSTRACT
Three previously unknown pentaketides, (+)-formylanserinone B (3), (-)-epoxyserinone A (4), and (+)-epoxyserinone B (5), along with two known fungal pigments, anserinones A (1) and B (2), were isolated and identified from a deep water (-4380 ft), marine-derived saltwater fungal culture. Two other minor constituents, hydroxymethylanserinone B (6) and deoxyanserinone B (7), were also isolated, but not completely purified. The structures of 3-7, each expanding the dense functionalization of the anserinones, were determined by dereplication and spectroscopic analysis. Bioactivity was explored in two separate cell-based assays. Leukemia selectivity was greatest with 2 and 3, while 1-3 exhibited modest activity against the MDA-MB-435 cell line.
Subject(s)
Benzoquinones/isolation & purification , Biological Factors , Fungi/chemistry , Penicillium/chemistry , Water Microbiology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Biological Factors/chemistry , Biological Factors/isolation & purification , Biological Factors/pharmacology , Drug Screening Assays, Antitumor , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Stereoisomerism , Tumor Cells, CulturedABSTRACT
Four novel bisulfide bromotyrosine derivatives, psammaplins E (9), F (10), G (11), and H (12), and two new bromotyrosine derivatives, psammaplins I (13) and J (14), were isolated from the sponge Pseudoceratina purpurea, along with known psammaplins A (4), B (6), C (7), and D (8) and bisaprasin (5). The structures of psammaplins E (9) and F (10), which each contain an oxalyl group rarely found in marine organisms, were determined by spectroscopic analysis. Compounds 4, 5, and 10 are potent histone deacetylase inhibitors and also show mild cytotoxicity. Furthermore, compounds 4, 5, and 11 are potent DNA methyltransferase inhibitors. The biogenetic pathway previously proposed for the psammaplins class is also revisited.
