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1.
Bioorg Med Chem ; 26(11): 2965-2972, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29567296

ABSTRACT

The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.


Subject(s)
Cysteine Endopeptidases/chemistry , Drug Discovery , Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis , Poly(ADP-ribose) Polymerases/chemistry , Allosteric Regulation , Carbazoles/chemistry , Humans , Inhibitory Concentration 50 , Models, Biological , Molecular Docking Simulation , Molecular Structure , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/drug effects , Structure-Activity Relationship
2.
ACS Chem Biol ; 12(11): 2866-2874, 2017 11 17.
Article in English | MEDLINE | ID: mdl-28991428

ABSTRACT

Macrodomains are conserved protein interaction modules that can be found in all domains of life including in certain viruses. Macrodomains mediate recognition of sequence motifs harboring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterization of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallization of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prevents its localization to sites of DNA damage.


Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Adenosine Diphosphate Ribose/metabolism , Allosteric Regulation/drug effects , Cell Line , DNA Damage/drug effects , Humans , Molecular Docking Simulation , Poly(ADP-ribose) Polymerases/chemistry , Protein Domains/drug effects
3.
Arch Pharm (Weinheim) ; 349(9): 710-23, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27503113

ABSTRACT

Based on the chemotype of canthin-4-one alkaloids with moderate antimicrobial activity, a collection of variously substituted canthin-4-ones and desaza analogs were synthesized. Key steps in the syntheses were regioselective halogenations of (desaza) canthin-4-one, followed by Pd-catalyzed cross-coupling reactions. The in vitro screening for antimicrobial activity revealed that two 5-substituted canthin-4-ones (3-pyridyl, 2-bromophenyl) exhibit significant activity against Streptococcus entericus, coupled with high selectivity and the lack of cytotoxicity against mammalian cells. The intact canthin-4-one ring system was demonstrated to be essential for antibacterial activity.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carbolines/pharmacology , Indole Alkaloids/pharmacology , Anti-Bacterial Agents/chemical synthesis , Carbolines/chemical synthesis , Carbolines/chemistry , Cell Death/drug effects , Cell Line, Tumor , Humans , Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Microbial Sensitivity Tests , Structure-Activity Relationship
4.
Arch Pharm (Weinheim) ; 348(2): 125-31, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25664630

ABSTRACT

1-Acetylcarbazoles are readily converted to 3-desazacanthin-4-ones upon treatment with Bredereck's reagent, but in contrast to canthin-4-ones, these do not undergo ring transformation reactions with guanidine. Only after N-protection (methyl or 2-(trimethylsilyl)ethoxymethyl group), 2-desaza analogues of the alkaloid annomontine are accessible via the enaminoketones obtained by condensation with Bredereck's reagent. One of the annomontine analogues is an inhibitor of the Plasmodium falciparum CDC-like kinases (CLK) and shows antimalarial activity.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Carbolines/chemical synthesis , Carbolines/pharmacology , Drug Design , Plasmodium falciparum/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Molecular Structure , Plasmodium falciparum/enzymology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism , Structure-Activity Relationship
5.
PLoS One ; 9(9): e105732, 2014.
Article in English | MEDLINE | ID: mdl-25188378

ABSTRACT

Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-ß-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.


Subject(s)
Antimalarials/pharmacology , Malaria, Falciparum/prevention & control , Plasmodium falciparum/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Protozoan Proteins/antagonists & inhibitors , Animals , Gene Expression Regulation, Developmental , Genes, Protozoan , Humans , Malaria, Falciparum/parasitology , Malaria, Falciparum/transmission , Phosphorylation , Plasmodium falciparum/genetics , Plasmodium falciparum/physiology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/genetics , Protozoan Proteins/chemistry , Protozoan Proteins/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/genetics , Structural Homology, Protein
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