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1.
Arch Pharm (Weinheim) ; 353(6): e1900320, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32285482

ABSTRACT

Human protein kinases have been established as promising druggable targets in cancer therapy. However, a large number of acquired drug-resistant kinase mutations are observed after first- and second-line kinase inhibitor treatments, largely limiting the application of small-molecule inhibitors in the targeted cancer therapy. Previously, the pan-kinase inhibitor staurosporine and its derivatives have been reported to selectively inhibit gatekeeper mutants over wild-type kinases, suggesting that the staurosporine scaffold is potentially helpful in developing wild-type-sparing inhibitors of drug-resistant kinase mutants. Here, a systematic response profile of 32 staurosporine scaffold-based inhibitors (SSBIs) for 61 ontology-enriched drug-resistant cancer kinase mutations is created using a combination of in silico analysis and in vitro assay, from which it is possible to identify those mutations that have the potential to cause resistance or confer sensitivity to SSBIs. The profile reveals that SSBIs exhibit distinct responses to kinase gatekeeper and nongatekeeper mutations, and SSBIs bearing p7 substituents can considerably influence their response to kinase gatekeeper mutations, particularly for the mutations of the Ile residue, which possesses a Cß methyl group that tends to cause steric clash with bound SSBIs. Nongatekeeper mutations generally have a moderate and unfavorable effect on SSBI activity, as most of them are outside the kinase active site and do not directly contact inhibitor ligands. In addition, it is found that resistance is commonly caused by mutation-induced hindrance effects, whereas sensitivity is primarily conferred by mutation-established additional interactions.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Staurosporine/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Mutation , Neoplasms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinases/genetics , Staurosporine/chemical synthesis , Staurosporine/chemistry , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 29(21): 126641, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31526603

ABSTRACT

Selectivity profiling of compounds is important for kinase drug discovery. To this end, we aimed to develop a broad-range protein kinase assay by synthesizing a novel staurosporine-derived fluorescent probe based on staurosporine and kinase-binding related structural information. Upon structural analysis of staurosporine with kinases, a 4'-methylamine moiety of staurosporine was found to be located on the solvent side of the kinases, to which several linker units can be conjugated by either alkylation or acylation. However, such conjugation was suggested to reduce the binding affinities of the modified compound for several kinases, owing to the elimination of hydrogen bond donor moiety of NH-group from 4'-methylamine and/or steric hindrance by acyl moiety. Based on this structural information, we designed and synthesized a novel staurosporine-based probe without methyl group in order to retain the hydrogen bond donor, similar to unmodified staurosporine. The broad range of the kinase binding assay demonstrated that our novel fluorescent probe is an excellent tool for developing broad-ranging kinase binding assay.


Subject(s)
Fluorescent Dyes/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Staurosporine/chemistry , Binding Sites , Binding, Competitive , Biosensing Techniques , Drug Evaluation, Preclinical/methods , Fluorescence Resonance Energy Transfer , Fluorescent Dyes/chemical synthesis , Humans , Hydrogen Bonding , Methylamines/chemistry , Molecular Structure , Protein Binding , Sensitivity and Specificity , Staurosporine/chemical synthesis , Structure-Activity Relationship
3.
J Nat Prod ; 81(8): 1745-1751, 2018 08 24.
Article in English | MEDLINE | ID: mdl-30106291

ABSTRACT

Two new staurosporine derivatives, staurosporines M1 and M2 (4 and 5), in addition to five previously reported metabolites (1-3, 6, and 7), were generated by the heterologous expression of engineered spc gene clusters in Streptomyces coelicolor M1146. The structures of these derivatives were determined by a combination of spectroscopic methods and CD measurement. Compounds 1, 2, 4, and 5 showed effective activities against three tumor cell lines (HCT-116, K562, and Huh 7.5), and 3 was active against HCT-116 and K562 cells. In addition, compounds 3 and 5 showed undetectable toxicity up to 100 µM toward the normal hepatic cell line LO2. Based on the IC50 values, their structure and activity relationships are discussed.


Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Staurosporine/analogs & derivatives , Staurosporine/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Circular Dichroism , Escherichia coli/genetics , Escherichia coli/metabolism , Genetic Engineering , Humans , Molecular Structure , Multigene Family/genetics , Staurosporine/pharmacology , Streptomyces coelicolor/genetics , Streptomyces coelicolor/metabolism , Structure-Activity Relationship
4.
Future Med Chem ; 9(15): 1709-1729, 2017 10.
Article in English | MEDLINE | ID: mdl-28925739

ABSTRACT

AIM: VEGFR2 tyrosine kinase is a main target in suppressing cancer growth and metastasis. Materials & methods: Piperazine-based thiazolidinones were synthesized and screened for their anticancer and VEGFR2 tyrosine kinase inhibitory activity. Results: Compounds 11, 13 and 16 displayed potent anticancer activity against HepG-2 with IC50 values 0.03-0.06 µM. They were safe on normal human fibroblasts with selectivity indices 8.09, 11.40 and 4.37, respectively. Also, these compounds showed VEGFR2 tyrosine kinase inhibitory activities more than the reference staurosporine with IC50 values <0.3 µM. Lineweaver-Burk plot revealed that these compounds behaved as uncompetitive VEGFR2 tyrosine kinase inhibitors. They also induced caspase-dependent apoptosis in HepG-2. In addition, these compounds revealed good binding within VEGFR2 tyrosine kinase enzyme in comparison with sorafenib reference. CONCLUSION: Compounds 11, 13 and 16 comprise a new promising scaffold of selective VEGFR2 tyrosine kinase inhibitors with caspase-dependent apoptotic activities.


Subject(s)
Apoptosis/drug effects , Piperazines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Thiazolidines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Binding Sites , Caspases/metabolism , Cell Line, Tumor , Hep G2 Cells , Humans , Molecular Docking Simulation , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/metabolism , Phenylurea Compounds/pharmacology , Piperazine , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Sorafenib , Staurosporine/chemical synthesis , Staurosporine/chemistry , Staurosporine/pharmacology , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/metabolism
5.
Bioorg Med Chem ; 24(14): 3116-24, 2016 07 15.
Article in English | MEDLINE | ID: mdl-27255178

ABSTRACT

A derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, was synthesized. The resulting indolopyrazolocarbazole (3) inhibited Pim isoforms 1-3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ. Compound 3 exhibited moderate cytotoxic activity toward human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with Pim activity.


Subject(s)
Pyrazoles/chemistry , Staurosporine/chemical synthesis , Staurosporine/pharmacology , Carbon-13 Magnetic Resonance Spectroscopy , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , K562 Cells , Models, Molecular , Protein Kinase C/drug effects , Protein Kinase C-alpha/drug effects , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Staurosporine/chemistry , Structure-Activity Relationship
6.
ChemMedChem ; 11(9): 972-9, 2016 05 06.
Article in English | MEDLINE | ID: mdl-27008372

ABSTRACT

The natural product staurosporine is a high-affinity inhibitor of nearly all mammalian protein kinases. The labelling of staurosporine has proven effective as a means of generating protein kinase research tools. Most tools have been generated by acylation of the 4'-methylamine of the sugar moiety of staurosporine. Herein we describe the alkylation of this group as a first step to generate a fluorescently labelled staurosporine. Following alkylation, a polyethylene glycol linker was installed, allowing subsequent attachment of fluorescein. We report that this fluorescein-staurosporine conjugate binds to cAMP-dependent protein kinase in the nanomolar range. Furthermore, its binding can be antagonised with unmodified staurosporine as well as ATP, indicating it targets the ATP binding site in a similar fashion to native staurosporine. This reagent has potential application as a screening tool for protein kinases of interest.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Fluorescent Dyes/chemistry , Protein Kinase Inhibitors/metabolism , Staurosporine/chemistry , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Alkylation , Binding Sites , Cyclic AMP-Dependent Protein Kinases/chemistry , Fluorescence Polarization , Protein Binding , Protein Kinase Inhibitors/chemistry , Staurosporine/chemical synthesis , Staurosporine/metabolism
7.
Eur J Med Chem ; 48: 108-13, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22182929

ABSTRACT

A novel series of indolocarbazoles were synthesized and their antiproliferative activity against HUVEC, LoVo, DLD-1 and ST-486 cell lines, was investigated. Those staurosporine analogs in which a substituted dimethylaminoalkoxy chain was attached to the indolic nitrogen showed interesting activity and selectivity with respect to HUVEC proliferation. The effect on capillary tube formation in 3-dimensional matrigel matrix was studied using the most active compounds. Evaluation of their in vivo anti-angiogenic activity in a murine Lewis lung cancer model was also analyzed.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Lung Neoplasms/blood supply , Lung Neoplasms/drug therapy , Staurosporine/analogs & derivatives , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Capillaries/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Collagen/pharmacology , Drug Combinations , Humans , Laminin/pharmacology , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Neovascularization, Pathologic/drug therapy , Proteoglycans/pharmacology , Spectrophotometry, Infrared , Staurosporine/chemical synthesis , Staurosporine/chemistry , Staurosporine/pharmacology
8.
Org Lett ; 13(6): 1418-21, 2011 Mar 18.
Article in English | MEDLINE | ID: mdl-21341756

ABSTRACT

A synthesis of staurosporine aglycon and its analogs was achieved in a 28-36% overall yield starting from 2-methylindole. The prominent key steps for the synthesis of the indolocarbazole alkaloids involved electrocyclization and nitrene insertion reactions.


Subject(s)
Carbazoles/chemical synthesis , Indoles/chemistry , Staurosporine/analogs & derivatives , Staurosporine/chemical synthesis , Bromides/chemistry , Catalysis , Cyclization , Molecular Structure , Staurosporine/chemistry , Zinc Compounds/chemistry
9.
Bioorg Med Chem Lett ; 19(12): 3333-8, 2009 Jun 15.
Article in English | MEDLINE | ID: mdl-19427203

ABSTRACT

The synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed completely de novo, and a ring closing metathesis strategy is used to assemble the sugar mimetic portion. These analogs show potent JAK3 activity against isolated enzyme and in T-cells. One analog (32) showed unique biological effects during in vitro and in vivo tests including inhibition of STAT5 phosphorylation, blockade of mast cell responses, and reduction of JAK3 based effects in mice models of allergic disease.


Subject(s)
Hypersensitivity/drug therapy , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Staurosporine/chemical synthesis , Animals , Cyclization , Drug Evaluation, Preclinical , Mast Cells/drug effects , Mice , Phosphorylation/drug effects , STAT5 Transcription Factor/metabolism , Structure-Activity Relationship , T-Lymphocytes/enzymology
10.
Org Biomol Chem ; 7(4): 706-16, 2009 Feb 21.
Article in English | MEDLINE | ID: mdl-19194586

ABSTRACT

Stable, water-soluble aminosugar staurosporine, K-252a and rebeccamycin analogs have been prepared by nucleophilic opening of C(2)-symmetric N-activated bis-aziridines by bis-indolylmaleimides. This divergent strategy allows the synthesis of unsymmetrical substituted derivatives and provides an easy access to the piperidine and pyrrolidine analogs.


Subject(s)
Aziridines/chemistry , Staurosporine/analogs & derivatives , Aza Compounds , Drug Stability , Piperidines , Pyrrolidines , Solubility , Staurosporine/chemical synthesis
11.
J Org Chem ; 72(6): 2008-14, 2007 Mar 16.
Article in English | MEDLINE | ID: mdl-17309305

ABSTRACT

We report a method for the synthesis of N-protected staurosporinones, which are useful for the synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids and related compounds. An interaction of gramine methiodide (2) with 3-(N-benzyl)indolylacetonitrile (3) in the presence of t-BuLi, followed by a CF3COOH-catalyzed intramolecular indole-indole coupling and dehydrogenation with DDQ, produced 5-cyanoindolo[2,3-a]carbazole 6 almost quantitatively. Reduction of its cyano group followed by N-benzylation produced N-benzylaminomethylindolo[2,3-a]carbazole 8b, which was subjected to Pd(OAc)2-catalyzed direct aromatic carbonylation to give N-protected staurosporinone 9b. Treatment with AlCl3 in anisole removed N-benzyl groups to afford staurosporinone quantitatively.


Subject(s)
Carbazoles/chemical synthesis , Indole Alkaloids/chemical synthesis , Staurosporine/chemical synthesis , Catalysis , Indoles , Ketones/chemical synthesis
12.
J Clin Pharmacol ; 45(4): 394-403, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15778420

ABSTRACT

UCN-01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half-life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN-01 to human alpha-1 acid glycoprotein much stronger than that to human serum albumin or human gamma-globulin. The association constants for alpha-1 acid glycoprotein and human plasma were approximately 8 x 10(8)(mol/L)(-1), indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN-01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Drugs, Investigational/pharmacology , Staurosporine/analogs & derivatives , Staurosporine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Drug Design , Drugs, Investigational/chemical synthesis , Drugs, Investigational/pharmacokinetics , Drugs, Investigational/therapeutic use , Humans , Staurosporine/chemical synthesis , Staurosporine/pharmacokinetics , Staurosporine/therapeutic use
13.
Bioorg Med Chem ; 6(9): 1597-604, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9801830

ABSTRACT

The indolocarbazole antibiotics staurosporine and rebeccamycin (1) are potent antitumor drugs targeting protein kinase C and topoisomerase I, respectively. To obtain staurosporine analogues from rebeccamycin, different structural modifications were performed: coupling of the sugar moiety to the second indole nitrogen, dechlorination and then reduction of the imide function to amide. The newly synthesized compounds (3-6) were tested for their abilities to bind to DNA and to inhibit topoisomerase I and protein kinase C. Their antiproliferative effects in vitro against B16 melanoma and P388 leukemia (including the related P388CPT cell line resistant to camptothecin) as well as their anti-HIV-1 and antimicrobial activities against various strains of microorganisms were determined. The cytotoxicity of the dechlorinated imide analogue 5 correlates well with its DNA binding and anti-topoisomerase I activities. These findings provide guidance for the development of new topoisomerase I-targeted antitumor indolocarbazoles equipped with a carbohydrate attached to the two indole nitrogens.


Subject(s)
Aminoglycosides , Anti-Bacterial Agents/chemistry , Carbazoles , Indoles , Staurosporine/analogs & derivatives , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Evaluation Studies as Topic , Humans , Magnetic Resonance Spectroscopy , Protein Kinase C/antagonists & inhibitors , Spectrophotometry, Infrared , Staurosporine/chemical synthesis , Staurosporine/pharmacology , Structure-Activity Relationship , Topoisomerase I Inhibitors , Tumor Cells, Cultured
14.
J Pharm Pharmacol ; 48(2): 160-71, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8935165

ABSTRACT

The synthesis of the 9 alpha- and 9 beta-epimers of 8, 9, 10, 11 alpha-tetrahydro-7 alpha H-7, 11-methano-12, 12-dimethylcycloocta [de] naphthyl-9-amine is described.


Subject(s)
Protein Kinase C/antagonists & inhibitors , Staurosporine/analogs & derivatives , Molecular Structure , Staurosporine/chemical synthesis , Staurosporine/chemistry
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