ABSTRACT
Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the fact that it inhibits tubulin polymerization. Additionally, it acts as an enhancer of depolymerization for taxol-stabilized tubulin. Western blot analyses of p53-positive cancer cells treated with compound 1 indicated upregulation of p53, p21, and p27 proteins together with downregulation of cyclin B1 and Cdk1. Compound 1 selectively induces apoptosis of SV40 large T-antigen transformed cells and significantly reduces colony formation efficiency, in a dose-dependent manner, of lung cancer cells. It is efficacious at 1/10th of the MTD against human tumors derived from HCT-116 and NCI-H460 cells in SCID mouse models. The promising efficacy of compound 1 in human xenograft models as well as its excellent therapeutic window indicates its potential for clinical development.
Subject(s)
Antineoplastic Agents/chemistry , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Drug Evaluation, Preclinical , Indoles/chemistry , Peptides, Cyclic/chemistry , Tubulin Modulators/chemistry , Animals , Cell Cycle , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Cyclin D1/chemistry , Dose-Response Relationship, Drug , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, SCID , Neoplasm Transplantation , Up-RegulationABSTRACT
A library of flavonol analogues was synthesised and evaluated as potential anticancer agents against a human prostate cancer cell line, 22rν1. Compounds 3, 8 and 11 (IC(50) 2.6, 3.3 and 4.0 µM respectively) showed potent cancer cell growth inhibition, comparable to the lead compound 3',4',5'-trimethoxyflavonol (1) (IC(50) 3.1 µM) and superior to the naturally occurring flavonols quercetin (16) and fisetin (22) (both >15 µM). Results indicate that the 3',4',5'- arrangement of either hydroxy (OH) or methoxy (OMe) residues is important for growth arrest of these cells and that the OMe analogues may be superior to their OH counterparts. Compounds 1, 3, 8 and 11 warrant further investigation as potential agents for the management of prostate cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Flavonols/chemical synthesis , Flavonols/pharmacology , Prostatic Neoplasms/pathology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor , Chemistry Techniques, Synthetic , Drug Stability , Flavonols/chemistry , Flavonols/pharmacokinetics , Humans , Hydrophobic and Hydrophilic Interactions , MaleABSTRACT
We present the design, synthesis and biological activity of a new series of substituted 3-(2-(1H-indol-1-yl)ethyl)-1H-indoles and 1,2-di(1H-indol-1-yl)alkanes as selective inhibitors of CDK4/cyclin D1. The compounds were designed to explore the relationship between the connection mode of the indolyl moieties and their CDK inhibitory activities. We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC(50) for the best compounds 10m and 13a being 39 and 37microm, respectively.
Subject(s)
Cyclin D1/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Binding Sites , Computer Simulation , Cyclin A/antagonists & inhibitors , Cyclin A/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/metabolism , Drug Design , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacologyABSTRACT
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme enzymes that catalyze the O(2)-dependent oxidation of L-tryptophan to N-formyl-kynurenine. Previous proposals for the mechanism of this reaction have suggested that deprotonation of the indole NH group, either by an active-site base or by oxygen bound to the heme iron, as the initial step. In this work, we have examined the activity of 1-Me-L-Trp with three different heme dioxygenases and their site-directed variants. We find, in contrast to previous work, that 1-Me-L-Trp is a substrate for the heme dioxygenase enzymes. These observations suggest that deprotonation of the indole N(1) is not essential for catalysis, and an alternative reaction mechanism, based on the known chemistry of indoles, is presented.
Subject(s)
Chemistry, Organic/methods , Dioxygenases/chemistry , Heme/chemistry , Catalysis , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Indoles/chemistry , Kinetics , Kynurenine/chemistry , Models, Chemical , Mutagenesis, Site-Directed , Oxygen/chemistry , Protons , Tryptophan/chemistry , Tryptophan Oxygenase/chemistryABSTRACT
We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-beta-carboline compounds related to the natural product fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the Suzuki-Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have a CDK4 IC(50) in the range 9-11 microM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a pi-stacking pocket within the active site of CDK4.
Subject(s)
Carbolines/chemical synthesis , Carbolines/pharmacology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Tryptamines/chemical synthesis , Tryptamines/pharmacology , Carbolines/chemistry , Cyclin-Dependent Kinase 4/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Spectrometry, Mass, Fast Atom Bombardment , Tryptamines/chemistryABSTRACT
Tryptamine derivatives, a new structural class of cyclin dependent kinase 4 inhibitors, have been identified during extensive biological screening of synthetic molecules. The molecules were synthesized based on the structure of fascaplysin, which is not only a specific inhibitor of the Cdk4-cyclin D1 enzyme but also a relatively toxic molecule, probably because it binds and intercalates DNA. Interestingly, the new structural analogues of fascaplysin do not interact or intercalate with double-stranded DNA, although they inhibit Cdk4-cyclin D1 specifically. We found that compound CA199 was the most potent molecule, showing at least 25-fold specificity towards Cdk4-cyclin D1 (IC50 for Cdk4-cyclin D1 = 20 microM, Cdk2 > 500 microM). CA199 inhibits the growth of different cancer cell lines at concentrations ranging from 10-40 microM. It blocks growth of asynchronous cells at G0/G1 in a retinoblastoma protein (pRb) dependent manner. Moreover, CA199 blocks growth only at early G1 in synchronised cells released from a mimosine-induced G1/S block. These observations are reminiscent of a true Cdk4 inhibitor.
Subject(s)
Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 4/chemistry , DNA/chemistry , DNA Topoisomerases, Type I/chemistry , DNA, Superhelical/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ethidium/chemistry , Flow Cytometry , Humans , Indoles/pharmacology , Nucleic Acid Conformation , Phosphorylation/drug effects , Retinoblastoma Protein/metabolismABSTRACT
The cleavage of two sugar epoxides, methyl 2,3-anhydro-alpha-D-mannopyranoside and 2,3-anhydro-alpha-D-allopyranoside, with amines is presented as a method for preparing a library of 3-amino-sugars (methyl 3-amino-3-deoxy-alpha-D-altropyranosides and methyl 3-amino-3-deoxy-alpha-D-glucopyranosides) as potential glycosidase inhibitors. Several of the altropyranosides were micromolar inhibitors of bovine liver beta-galactosidase and almond beta-glucosidase. X-ray crystal structures were determined for one of the methyl 3-amino-3-deoxy-alpha-D-altropyranosides, 4t, and one of the methyl 3-amino-3-deoxy-alpha-D-glucopyranosides, 6d.
Subject(s)
Amino Sugars/chemistry , Amino Sugars/chemical synthesis , Epoxy Compounds/chemistry , Glycoside Hydrolases/metabolism , Amino Sugars/pharmacology , Animals , Cattle , Crystallography, X-Ray , Glycoside Hydrolases/antagonists & inhibitors , Liver/enzymology , Molecular StructureABSTRACT
The intramolecular arene-olefin photoannulation reaction of diastereopure substrates and gave diastereopure and whose structures were determined by spectroscopic methods and confirmed by X-ray crystallography.
ABSTRACT
The synthesis of a series of beta-carboline-based analogues of the natural product fascaplysin is presented; the compounds were produced using a novel photo-oxidation reaction of 1-benzyl-4,9-dihydro-3H-beta-carbolines as the key step.
Subject(s)
Carbolines/chemistry , Hydrogen/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Oxidation-ReductionABSTRACT
Tryptamine derivatives, non-planar and potentially less toxic analogues of the anti-cancer agent fascaplysin, have been synthesised. They specifically inhibit Cdk4-D1 vis a vis Cdk2-A but, unlike fascaplysin, do not bind or intercalate DNA. CA224 is the most potent compound identified (Cdk4-D1 IC(50) approximately 5.5 microM). As would be expected of a Cdk4 inhibitor that does not inhibit Cdk2, it maintains a G(0)/G(1) block in synchronised cancer cells and inhibits Cdk4-specific phosphorylation of the retinoblastoma protein.
Subject(s)
Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/metabolism , Indoles/chemistry , Indoles/pharmacology , Retinoblastoma Protein/metabolism , Biphenyl Compounds/chemical synthesis , Chemistry, Pharmaceutical , DNA/chemistry , Drug Design , G1 Phase , Indoles/chemical synthesis , Inhibitory Concentration 50 , Models, Chemical , Phosphorylation , Resting Phase, Cell CycleABSTRACT
We present the design, synthesis, and biological activity of three classes of tryptamine derivatives, which are non-planar analogues of the toxic anti-cancer agent fascaplysin. We show these compounds to be selective inhibitors of CDK4 over CDK2, the most active compound has an IC50 for the inhibition of CDK4 of 6 microM.
Subject(s)
Chemistry, Organic/methods , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Amino Acid Sequence , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Drug Design , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/metabolism , Inhibitory Concentration 50 , Molecular Sequence Data , Molecular Structure , Tryptamines/chemistryABSTRACT
The design, synthesis and biological activity of a series of non-planar dihydro-beta-carboline and beta-carboline-based derivatives of the toxic anticancer agent fascaplysin is presented. We show these compounds to be selective inhibitors of CDK4 over CDK2 with an IC50 (CDK4-cyclin D1) = 11 micromol for the best compound in the series 4d. The crystallographic analysis of some of the compounds synthesised (3b/d and 4a-d) was carried out, in an effort to estimate the structural similarities between the designed inhibitors and the model compound fascaplysin.
Subject(s)
Carbolines/chemistry , Cyclin D1/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Carbolines/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Indoles/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular StructureABSTRACT
The first biologically active non-planar analogues of the toxic anti-cancer agent, fascaplysin, have been produced; we present the design, synthesis and biological activity of three tryptamine derivatives.
Subject(s)
Antineoplastic Agents/chemistry , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Indoles/chemistry , Proto-Oncogene Proteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase 4 , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Models, Molecular , Tyramine/analogs & derivatives , Tyramine/chemical synthesis , Tyramine/chemistryABSTRACT
Intramolecular [2 + 2] photoannulation catalysed by copper(i)triflate has been applied to a series of carbohydrate derivatives obtained from glucose. Dienes 1a and 1b lead to cyclobutanes 3a and 3b whereas the diastereoisomeric dienes 5a and 5b gave diastereoisomeric products 7a and 7b. These results demonstrate that the reaction is stereospecific. Products 3a and 7a were converted into bromoesters 4 and 9 respectively. The Vasella elimination of 8 lead to the expected bicyclic aldehyde 10 and the ring expanded hydroxy ketone 12. The stereospecific formation of enantiomerically pure spiro annulated carbohydrates 18a and 18b was demonstrated whereas in example 19 no selectivity in the formation of 20 and 21 was observed.
Subject(s)
Carbohydrates/chemical synthesis , Copper/chemistry , Glucose/analogs & derivatives , Glucose/chemistry , Carbohydrate Conformation , Catalysis , Molecular Sequence Data , Oxidation-Reduction , Photochemistry , StereoisomerismABSTRACT
The Fischer indole synthesis occurs in high yield with one equivalent of the ionic liquid choline chloride[middle dot]2ZnCl(2); exclusive formation of 2,3-disubstituted indoles is observed in the reaction of alkyl methyl ketones, and the products readily sublime directly from the ionic liquid.
ABSTRACT
Even eight-membered rings (such as in 2) can be formed by ring-closing metathesis of glucose derivatives such as 1. Enantiomerically pure tricyclic spiro compounds can also be prepared.
