A potent and highly selective inhibitor of human alpha-1,3-fucosyltransferase via click chemistry

Potent inhibitors of fucosyltransferases, and glycosyltransferases in general, have been elusive due to the inherent barriers surrounding the family of glycosyltransfer reactions. The problems of weak substrate affinity and low catalytic proficiency of fucosyltransferase was offset by recruiting additional binding features, in this case hydrophobic interactions, to produce a high affinity inhibitor, 24, with Ki = 62 nM. The molecule was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene reactants, followed by in situ screening without product isolation.     

KNI-272, a highly selective and potent peptidic HIV protease inhibitor

Kynostatin {KNI-272; systematic name: 3-[3-benzyl-2-hydroxy-9-(isoquinolin-5-yl­oxy)-6-methyl­sulfanyl­methyl-5,8-dioxo-4,7-di­aza­nonanoyl]-N-tert-butyl-1,3-thia­zolane-4-carbox­amide}, a highly selective and potent HIV protease inhibitor containing allo­phenyl­norstatin [(2S,3S)-3-amino-2-hydroxy-4-phenyl­butyric acid], has been crystallized as the hydrate, C₃₃H₄₁N₅O₆S₂·0.803H₂O, from aqueous hexyl­ene glycol. The observed disorder of the phenyl group in the structure is related to the mode of hydration. The backbone conformation of the mol­ecule is twisted and the overall conformation of the free inhibitor is similar to that observed in its complex with HIV protease.     

A highly potent and selective PKCalpha inhibitor generated via combinatorial modification of a peptide scaffold

A potent and highly selective inhibitor of protein kinase C alpha has been generated via the combinatorial modification of a consensus sequence peptide. The inhibitor displays a Ki of 800 pM versus variable peptide substrate and good selectivity versus other members of the PKC family, including PKCbeta (385-fold), PKCgamma (580-fold), PKCdelta (2730-fold), PKCepsilon (600-fold), PKCeta (1310-fold), PKCtheta (1210-fold), PKCiota (940-fold), and PKCzeta (640-fold). The parallel synthesis strategy employed is easily automated and straightforward to implement.     

A highly efficient synthesis of potent and selective butyrolactam inhibitors of 11beta-HSD1

A convergent synthesis of structurally novel butyrolactam 11beta-HSD1 inhibitors is described. The approach features an efficient Ireland-Claisen reaction to construct a highly substituted aldehyde building block which is converted to a lactam via a tandem reductive amination/cyclization sequence. The generality of the synthetic sequence is demonstrated during the preparation of two additional potent 11beta-HSD1 inhibitors.     

Synthesis of a potent and selective inhibitor of p90 Rsk

[reaction: see text] The synthesis of the naturally occurring kaempferol glycoside SL0101 has been accomplished, as has its biochemical evaluation. SL0101 exhibits selective and potent p90 Rsk inhibitory activity at nanomolar concentrations without inhibiting the function of upstream kinases such as MEK, Raf, or PKC. The synthesis verified the structural assignment of the natural product and has provided access to material sufficient for detailed biological evaluation.     

Tetrasubstituted phenanthrolines as highly potent, water-soluble, and selective g-quadruplex ligands

Small molecules capable of stabilizing the G-quadruplex (G4) structure are of interest for the development of improved anticancer drugs. Novel 4,7-diamino-substituted 1,10-phenanthroline-2,9-dicarboxamides that represent hybrid structures of known phenanthroline-based ligands have been designed. An efficient synthetic route to the compounds has been developed and their interactions with various G4 sequences have been evaluated by F?rster resonance energy transfer (FRET) melting assays, fluorescent intercalator displacement (FID), electrospray ionization mass spectrometry (ESI-MS), and circular dichroism (CD) spectroscopy. The preferred compounds have high aqueous solubility and are strong and potent G4 binders with a high selectivity over duplex DNA; thus, they represent a significant improvement over the lead compounds. Two of the compounds are inhibitors of HeLa and HT1080 cell proliferation.     

A potent and selective inhibitor of KIAA1363/AADACL1 that impairs prostate cancer pathogenesis

Cancer cells show alterations in metabolism that support malignancy and disease progression. Prominent among these metabolic changes is elevations in neutral ether lipids (NELs). We have previously shown that the hydrolytic enzyme KIAA1363 (or AADACL1) is highly elevated in aggressive cancer cells, where it plays a key role in generating the monoalkylglycerol ether (MAGE) class of NELs. Here, we use activity-based protein profiling-guided medicinal chemistry to discover a highly potent and selective inhibitor of KIAA1363, the carbamate JW480. We show that JW480, and an shRNA probe that targets KIAA1363, reduce MAGEs and impair the migration, invasion, survival, and in?vivo tumor growth of human prostate cancer cell lines. These findings indicate that the KIAA1363-MAGE pathway is important for prostate cancer pathogenesis and designate JW480 as a versatile pharmacological probe for disrupting this pro-tumorigenic metabolic pathway.     

A highly potent non-nucleoside adenosine deaminase inhibitor: efficient drug discovery by intentional lead hybridization

We disclose herein the rapid discovery of the first highly potent (Ki = 7.7 nM) non-nucleoside adenosine deaminase (ADA) inhibitor based on the rational hybridization of two structurally distinct leads. Two micromolar inhibitors were discovered by a parallel rational design and random screening program, and individual crystal structures of bovine ADA in complexation with these inhibitors revealed several unknown binding sites and distinct binding modes. Using this information as the starting point, highly effective lead hybridization was achieved in only two structure-based drug design iterations. The conceptual approach illustrated by this example promises to be broadly useful in the search for new chemical entities and can contribute greatly to improve the overall efficiency and speed of drug discovery.     

Understanding the inhibitory effect of highly potent and selective archazolides binding to the vacuolar ATPase

Vacuolar ATPases are a potential therapeutic target because of their involvement in a variety of severe diseases such as osteoporosis or cancer. Archazolide A (1) and related analogs have been previously identified as selective inhibitors of V-ATPases with potency down to the subnanomolar range. Herein we report on the determination of the ligand binding mode by a combination of molecular docking, molecular dynamics simulations, and biochemical experiments, resulting in a sound model for the inhibitory mechanism of this class of putative anticancer agents. The binding site of archazolides was confirmed to be located in the equatorial region of the membrane-embedded V(O)-rotor, as recently proposed on the basis of site-directed mutagenesis. Quantification of the bioactivity of a series of archazolide derivatives, together with the docking-derived binding mode of archazolides to the V-ATPase, revealed favorable ligand profiles, which can guide the development of a simplified archazolide analog with potential therapeutic relevance.     

Total synthesis of SR 121463 A, a highly potent and selective vasopressin v(2) receptor antagonist

SR 121463 A, 1, is a promising nonpeptide prototype for potent and selective antagonism of the vasopressin V(2) receptor subtype and, thus, a candidate for control of the clinically debilitating condition of hyponatremia and its associated syndromes. In the present work, we present a novel and stereoselective synthesis that stems from the preparation of three key intermediates: the substituted benzenesulfonyl chloride 2, the N-protected oxindole 3, and protected dibromide 4. The synthesis of 1 has been achieved in good overall yield, each step proceeding in greater than 80% yield. In addition, intermediate 2 and the syn isomer of 1 were prepared with complete control of stereochemistry. The latter reduction appears to proceed by lithium cation mediated chelation control. Molecular mechanics calculations with the MM3* and MMFF force fields underscore geometric and energetic aspects of the reaction.     

A highly sensitive and selective chemosensor for cyanide

A highly sensitive and selective cyanide chemosensor based on fused indoline and benzooxazine fragment was reported with fast response. The detection of cyanide was performed via the nucleophilic attack of cyanide anion on the oxazine. (1)H NMR and MS studies confirmed the cleavage of C-O bond of oxazine and binding of cyanide to the spiro center of oxazine. The specific reaction results in high selectivity for cyanide ion. Addition of cyanide anion to the oxazine in MeCN/H(2)O solution results in a loss in absorbance at 343 nm and an increase in new absorbance at 411 nm, thus resulting in obvious color changes. Cyanide can be detected down to 1 microM levels in a fast response of less than 30s with no interference of other anionic species. The cyanide detection method should have potential application in a variety of settings requiring rapid and accurate analysis of cyanide anion for drinking and fresh water.     

Preparation of non-peptide,highly potent and selective antagonists of arginine vasopressin V1A receptor by introduction of alkoxy groups

A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2'-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V1A receptors. Consequently, we found that the (Z)-4'-([4,4-Difluoro-5-[(4-dimethylaminopiperidino)carbonylmethylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl]carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4'-[(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper.