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1.
Cell Chem Biol ; 28(10): 1460-1473.e15, 2021 10 21.
Article in English | MEDLINE | ID: mdl-34015309

ABSTRACT

Cytoplasmic dyneins are AAA (ATPase associated with diverse cellular activities) motor proteins responsible for microtubule minus-end-directed intracellular transport. Dynein's unusually large size, four distinct nucleotide-binding sites, and conformational dynamics pose challenges for the design of potent and selective chemical inhibitors. Here we use structural approaches to develop a model for the inhibition of a well-characterized S. cerevisiae dynein construct by pyrazolo-pyrimidinone-based compounds. These data, along with functional assays of dynein motility and mutagenesis studies, suggest that the compounds inhibit dynein by engaging the regulatory ATPase sites in the AAA3 and AAA4 domains, and not by interacting with dynein's main catalytic site in the AAA1 domain. A double Walker B mutation of the AAA3 and AAA4 sites substantially reduces enzyme activity, suggesting that targeting these regulatory domains is sufficient to inhibit dynein. Our findings reveal how chemical inhibitors can be designed to disrupt allosteric communication across dynein's AAA domains.


Subject(s)
Dyneins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Small Molecule Libraries/metabolism , Allosteric Regulation/drug effects , Binding Sites , Catalytic Domain , Cryoelectron Microscopy , Dyneins/chemistry , Dyneins/genetics , Humans , Molecular Docking Simulation , Mutagenesis, Site-Directed , Protein Binding , Pyrazoles/chemistry , Pyrazoles/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/genetics , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology
2.
J Med Chem ; 63(18): 10352-10379, 2020 09 24.
Article in English | MEDLINE | ID: mdl-32900194

ABSTRACT

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic ß-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.


Subject(s)
Benzamides/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/therapeutic use , Piperidines/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , CHO Cells , Cricetulus , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice, Inbred ICR , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship
3.
Bioorg Med Chem ; 26(9): 2452-2465, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29669694

ABSTRACT

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Serine C-Palmitoyltransferase/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , High-Throughput Screening Assays , Humans , Mice , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacokinetics , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor Assays
4.
Bioorg Med Chem ; 25(12): 3018-3033, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28392276

ABSTRACT

In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.


Subject(s)
Cyclin-Dependent Kinase 8/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase 8/metabolism , Cyclin-Dependent Kinases/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Female , Humans , Mice , Molecular Docking Simulation , Neoplasms/metabolism , Neoplasms/pathology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology
5.
Biochem Biophys Res Commun ; 484(3): 493-500, 2017 03 11.
Article in English | MEDLINE | ID: mdl-28108287

ABSTRACT

Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin. In the presence of compound-2, exogenously added S1P partially compensated the intracellular sphingolipid levels through the salvage pathway by partially rescuing compound-2-induced cytotoxicity. This suggested that the mechanism underlying the anti-proliferative effect of compound-2 involved the reduction of sphingolipid levels. Indeed, compound-2 promoted multinuclear formation with reduced endogenous sphingomyelin levels specifically in a compound-2-sensitive cell line, indicating that the effect was induced by sphingolipid reduction. Furthermore, compound-2 showed potent antitumor activity without causing significant body weight loss in the PL-21 acute myeloid leukemia mouse xenograft model. Therefore, SPT may be an attractive therapeutic anti-cancer drug target for which compound-2 may be a promising new drug.


Subject(s)
Antineoplastic Agents/administration & dosage , Enzyme Inhibitors/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Serine C-Palmitoyltransferase/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice , Mice, SCID , Mouth/metabolism , Treatment Outcome
6.
J Am Chem Soc ; 132(29): 10070-7, 2010 Jul 28.
Article in English | MEDLINE | ID: mdl-20608657

ABSTRACT

Cyanoformates and cyanoformamides are found to add across alkynes by nickel/Lewis acid (LA) cooperative catalysis to give beta-cyano-substituted acrylates and acrylamides, respectively, in highly stereoselective and regioselective manners. The resulting adducts serve as versatile synthetic building blocks through chemoselective transformations of the ester, amide, and cyano groups as demonstrated by the synthesis of typical structures of beta-cyano ester, beta-amino nitrile, gamma-lactam, disubstituted maleic anhydride, and gamma-aminobutyric acid. The related reactions of cyanoformate thioester and benzoyl cyanide, on the other hand, are found to add across alkynes with decarbonylation in the presence of a palladium/LA catalyst.

7.
J Am Chem Soc ; 131(31): 10964-73, 2009 Aug 12.
Article in English | MEDLINE | ID: mdl-19722672

ABSTRACT

Allyl cyanides are found to add across alkynes in the presence of a nickel/P(4-CF(3)-C(6)H(4))(3) catalyst to give polysubstituted 2,5-hexadienenitriles with defined stereo- and regiochemistry. Use of AlMe(2)Cl or AlMe(3) as a Lewis acid cocatalyst accelerates the reaction and expands the substrate scope significantly. The cyano group in the allylcyanation products can be transformed to a hydroxymethyl or aminomethyl group to afford highly substituted allylic alcohols or amines. Alpha-siloxyallyl cyanides also add across alkynes selectively at the less hindered gamma-carbon to allow introduction of 3-oxo-propyl functionality after hydrolysis of the resulting silyl enol ethers. This particular carbocyanation reaction has been applied to the stereoselective construction of the trisubstituted double bond of plaunotol, an antibacterial natural product active against Helicobacter pylori.

8.
J Am Chem Soc ; 131(18): 6624-31, 2009 May 13.
Article in English | MEDLINE | ID: mdl-19378963

ABSTRACT

Cyanoformate esters add across 1,2-dienes in the presence of a nickel/PMe(2)Ph catalyst to afford beta-cyano-alpha-methylenealkanoates regioselectively, which are kinetically favored and readily isomerize to thermodynamically favored alpha-cyanomethyl-alpha,beta-unsaturated carboxylates at high temperature under the nickel catalysis, possibly through oxidative addition of the C-CN bond. Similar cyanoesterification products are produced from chloroformate esters, trimethylsilyl cyanide, and 1,2-dienes in the presence of a nickel/dppp catalyst. The resulting cyanoesterification products have a structure of allylic cyanide and thus undergo further allyl cyanation reaction across alkynes with the aid of a nickel/P(4-CF(3)-C(6)H(4))(3) catalyst to afford highly substituted acrylonitrile derivatives.

10.
J Am Chem Soc ; 128(23): 7420-1, 2006 Jun 14.
Article in English | MEDLINE | ID: mdl-16756278

ABSTRACT

A Ni/PMe2Ph catalyst is found to effect regioselective addition of cyanoformate esters across 1,2-dienes, giving rise to 3-alkoxycarbonyl-3-butenenitriles. Functional groups such as cyano, protected hydroxyl, and amino groups in the 1,2-diene substrates are tolerated. Isomerization of the initial products to thermodynamically more stable isomers takes place possibly through further oxidative addition of the C-CN bond of 3-alkoxycarbonyl-3-butenenitriles to Ni(0) followed by reductive elimination. The cyanoesterification products undergo further addition across alkynes in the presence of a Ni/P(4-CF3-C6H4)3 catalyst.


Subject(s)
Alkadienes/chemistry , Cyanates/chemistry , Esters/chemistry , Methacrylates/chemical synthesis , Nitriles/chemical synthesis , Catalysis , Isomerism , Models, Chemical , Transition Elements/chemistry
11.
J Am Chem Soc ; 128(22): 7116-7, 2006 Jun 07.
Article in English | MEDLINE | ID: mdl-16734437

ABSTRACT

Allyl cyanides are found to add across alkynes in the presence of a nickel catalyst prepared from Ni(cod)2 and P(4-CF3-C6H4)3 in situ to give variously functionalized di- or trisubstituted acrylonitriles in highly stereoselective manners possibly via a pi-allylnickel species as an intermediate. alpha-Siloxyallyl cyanides also react at the gamma-position of a cyano group with both internal and terminal alkynes having various functional groups to give silyl enol ethers, which give the corresponding aldehydes or ketones upon hydrolysis.

12.
J Phys Chem B ; 109(44): 20817-23, 2005 Nov 10.
Article in English | MEDLINE | ID: mdl-16853698

ABSTRACT

The energetics and the electronic and magnetic properties of iridium nanoparticles in the range of 2-64 atoms were investigated using density functional theory calculations. A variety of different geometric configurations were studied, including planar, three-dimensional, nanowire, and single-walled nanotube. The binding energy per atom increases with size and dimensionality from 2.53 eV/atom for the iridium dimer to 6.09 eV/atom for the 64-atom cluster. The most stable geometry is planar until four atoms are reached and three-dimensional thereafter. The simple cubic structure is the most stable geometric building block until a strikingly large 48-atom cluster, when the most stable geometry transitions to face-centered cubic, as found in the bulk metal. The strong preference for cubic structure among small clusters demonstrates their rigidity. This result indicates that iridium nanoparticles intrinsically do not favor the coalescence process. Nanowires formed from linear atomic chains of up to 4-atom rings were studied, and the wires formed from 4-atom rings were extremely stable. Single-walled nanotubes were also studied. These nanotubes were formed by stacking 5- and 6-atom rings to form a tube. The ring stacking with each atom directly above the previous atom is more stable than if the alternate rings are rotated.

13.
J Am Chem Soc ; 126(48): 15650-1, 2004 Dec 08.
Article in English | MEDLINE | ID: mdl-15571380

ABSTRACT

Palladium-iminophosphine complex catalyzes stannylative cycloaddition of conjugated enynes using hexabutyldistannoxane as a stannylating agent to afford highly substituted 3-alkenylphenylstannanes regioselectively. Stannylative cross-cycloaddition reactions between different enynes or between enynes and diynes are also achieved. The reaction is successfully applied to a concise synthesis of alcyopterosin N, which has been isolated recently from sub-Antarctic soft coral, Alcyonium paessleri.

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