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As an effective strategy of the drug discovery for peptide-binding GPCRs based on the natural ligands, beta-turn peptidomimetic compound library with benzodiazepine skeleton was constructed using solid and solution phase parallel synthesis with four different scaffolds containing Phe, Lys, Ser and Glu, respectively. The usefulness of 162 library compounds was evaluated by the cell based screening at melanocortin 4 receptor in CHO-k1 cells, to find hit compounds showing agonistic effect at the receptor. The screening of library afforded three hit compounds including the most effective analog, (S)-3-benzyl-7-(4-fluorobenzyloxy)-4-(4-methoxyphenethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one, 13aiE, of which EC50 was determined as 13 μM.

We report the design and synthesis of an insulin receptor kinase family-targeted inhibitor template using the inhibitor conformation observed in an IGF1R/inhibitor co-crystal complex by application of a novel molecular design approach that we have recently published. The synthesis of the template involves a one pot Opatz cyclization reaction that provides a versatile indole ester in good yields. We also developed the required chemistry to elaborate this template with additional substituents and have used this chemistry to prepare some initial compounds that show selective inhibition of anaplastic lymphoma kinase (ALK).

We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogues. We present results on the in vitro activity for this compound against several tumor cell lines.

The beta-turn has been implicated as an important conformation for biological recognition of peptides or proteins. We adapted the concept of general Calpha atom positioning from the cluster analysis and recombination of each ideal beta-turn conformation pattern by Garland and Dean (J. Comput.-Aided Mol. Des. 1999, 13, 469) as one strategy of designing non-peptide beta-turn scaffolds. Herein, the Calpha positions of tetrahydro-1,4-benzodiazepin-2-one scaffold were analyzed after the calculation of the low-energy conformer using a semiempirical protocol. Three points of corresponding Calpha carbons for diverse substitutions in the scaffold were designated, and an efficient solid-phase synthesis of the peptidomimetic library was developed. The scaffold itself was synthesized in solution phase starting from 5-hydroxy-2-nitrobenzaldehyde and loaded to the 4-formyl-3,5-dimethoxyphenoxy (PL-FDMP) resin with high efficiency of reductive amination. Various building blocks for the derivatization of the 7-hydroxyl and N-1 amide nitrogen could be introduced via selective alkylation. Cleavage, parallel column chromatography, and NMR analysis of 62 final compounds confirmed the feasibility of this peptidomimetic library synthesis.

The coordination chemistry of silver(I) with the nitrogen-bridged ligands (C6H5)2PN(R)P(C6H5)2 [R = H (dppa); R = CH3 (dppma)] has been investigated by 31P NMR and electrospray mass spectrometry (ESMS). Species observed by 31P NMR include Ag2(μ-dppa)2+, Ag2(μ-dppa)22+, Ag2(μ-dppa)32+, Ag2(μ-dppma)2+, Ag2(μ-dppma)22+, and Ag(η2-dppma)2+. Species observed by ESMS at low cone voltages were Ag2(dppa)22+, Ag2(dppa)32+, Ag2(dppma)22+, and Ag(dppma)2+. (C6H5)2PN(CH3)P(C6H5)2 showed a strong tendency to chelate, while (C6H5)2PN(H)P(C6H5)2 preferred to bridge. Differences in the bridging versus chelating behavior of the ligands are assigned to the Thorpe−Ingold effect, where the methyl group on nitrogen sterically interacts with the phenyl groups on phosphorus. The crystal structure of the three-coordinate dinuclear silver(I) complex {Ag2[(C6H5)2PN(H)P(C6H5)2]3}(BF4)2 has been determined. Bond distances include Ag−Ag = 2.812(1) A, Ag(1)−P(av) = 2.492(3) A, and Ag(2)−P(av) = 2.509(3) A. The compound crystallizes in...

Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels–Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.

N-aryl androsterone pyrazoles, which showed a good inhibitory activity against aromatasc, were synthesized.

Some of the synthesized compounds exhibit single digit micromolecular inhibition of ALK in vitro.

A library of diarylurea insulin-like growth factor 1 receptor inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.

Mo 2 (O 2 CCF 3 ) 4 reacts with (unsymmetrical) N,N-dimethylethylenediamine (udmed) in ethanol or acetonitrile to form a crystalline product. Solid-state IR studies both bridging bidentate and ionic trifluoroacetates. A single-crystal X-ray study of the orange blades indicates that the complex exists as [Mo 2 (O 2 CCF 3 ) 3 (Me 2 NCH 2 CH 2 -NH 2 ) 2 ] (O 2 CCF 3 ), in which the two udmed ligands bind as axial-equatorial chelates to each of the metals

Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diaryl ethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >300 member library, which was subsequently screened to establish the SAR for esterase inhibition. This allowed the identification of single digit nanomolar hiCE inhibitors that showed improvement in both selectivity and measured solubility.

C 24 H 27 O 6 P cristallise dans Pbca avec a=7,615, b=20,087, c=29,447 A, Z=8; affinement jusqu'a R=0,0568. Les longueurs des liaisons P-C sont legerement allongees par rapport a celles du triphenylphosphine. Les angles des liaisons C-P-C sont seulement legerement plus grands que ceux du triphenylphosphine. Le plan d'un cycle aromatique est vraiment perpendiculaire au plan defini par les trois atomes C lies a l'atome P alors que les deux autres cycles sont inclines

We report the practical synthesis and structural characterization of a set of conformationally constrained protected arginine analogues. These enantiomerically pure analogues have the general structure 1 and are prepared in seven to eight steps from the commercially available isomers of 4-hydroxyproline. These analogues vary in side chain length and in relative and absolute stereochemistry and are suitable for the direct introduction into peptides. The resulting peptide analogues should be useful as enzymatically stable replacements for bioactive peptides and as probes for understanding the conformational aspects of protein-peptide interactions

Quadruply bonded dimolybdenum complexes Mo 2 (S 2 PF 2 ) 4 , Mo 2 (S 2 PF 2 ) 2 (O 2 CCF 3 ) 2 , Mo 2 (S 2 PF 2 ) 2 (O 2 CMe) 2 and Mo 2 (S 2 PMe 2 ) 4 have been prepared by the stoichiometric reaction between molybdenum acetate or molybdenum trifluoroacetate and the ligand. The solid complexes have been characterized by elemental analyses, infrared spectroscopy, 19 F and 31 p nmr spectroscopy and mass spectrometry. Trifluoroacetate, PF 2 S 2 − and acetate act as bidentate bridging ligands in all of the complexes. Coordinating solvents such as acetonitrile, pyridine and dimethylsulfoxide rapidly displace PF 2 S 2 − but not the acetate or trifluoroacetate ligands. For Mo 2 (S 2 PMe 2 ) 4 , two species have been observed by 31 P nmr in non-coordinating solvents. The major species is the all-ligand-bridged C 4h isomer; the minor species is the C 2v isomer in which two ligands bridge the Mo 2 core and two ligands chelate to one Mo.

Oxygenated derivates of cholesterol and lanosterol, known as oxysterols, have consistently displayed significant activity as inhibitors of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, a key regulatory enzyme in sterol biosynthesis. We have developed the chemical syntheses of ring C oxysterols for evaluation as inhibitors of sterol biosynthesis. A key intermediate in the chemical synthesis was 3beta-benzoyloxy-9alpha, 1alpha-epoxy-5alpha-cholest-7-ene (1), whose structure was confirmed by X-ray crystallographic analysis and is presented herein.

The synthesis of tris(2,6-dihydroxyphenyl)amine diborate, 4, is reported. This compound contains a linear B...N...B array for which a symmetrical three-center two-electron (3c-2e) bond is possible. The X-ray crystal structure of 4 shows that 3c-2e bonding is, in fact, absent. Rather, the B-N-B array of 4 is unsymmetrical, having a 2c-2e B-N dative bond with the remaining boron pyramidalized outward and bonded to the oxygen of THF, i.e., 4 x THF. In THF solution, 4 displays temperature-dependent 13C NMR spectra from which a DeltaG++ of 11.6 kcal/mol at 262 K may be calculated. The dynamic process observed in solution corresponds to a bond-switching equilibrium in which the B-N bond oscillates between the two borons ("bell clapper"). Ab initio calculations indicate that the most likely pathway for the bond switch does not involve a 3c-2e B...N...B bond, but rather occurs by nucleophilic attack of THF on the datively bonded boron to generate 4 x (THF)2, lacking any B-N interactions, followed by loss of one THF. The B-N-B system of 4 sans the perturbing effect of solvent was also investigated computationally. The form of 4 containing a 3c-2e bond is found to be a transition state in the solvent-free bond-switch reaction of 4, lying 2.66 kcal/mol above 4. The stability of three-center bonds to in-line distortion (viz., X...Y...X --X-Y.........X) is discussed from the point of view of the second-order Jahn-Teller effect.

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.

A series of benzoylpyrimidines derived from the anilinepyrimidine CRF(1) antagonists were synthesized. Several synthetic routes were developed to explore the SAR of this series of compounds. Compounds such as 8d (K(i) = 15 nM) exhibited high binding affinities at the human CRF(1) receptor.

A series of 4-substituted 8-aryl-2-methylquinolines 4 was designed and synthesized as highly potent antagonists for the human CRF(1) receptor. This series of compounds displayed parallel SAR to other bicyclic systems such as pyrazolo[1,5-a]pyrimidines, with several compounds possessing low nanomolar binding affinity. In addition to the high potency, the basicity of this 4-aminoquinoline core may offer CRF(1) antagonists with lower lipophilicity.

A series of 2-dialkylamino-4-phenylpyrimidines (7) was designed and synthesized as CRF(1) antagonists. SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl)amino group.

Nonpeptide compounds that mimic bioactive peptides are desirable for a number of clinical indications. We report a new practical method for the design of scaffolds exhibiting drug-like properties that are suitable for the display of peptide pharmacophores. The synthesis of various synthons of 7'-hydroxy-2',3'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,4'-quinoline]-2,5-dione (1) and methods for the introduction of several mimics of amino acid side-chains are described. This method is exemplified by derivatives that show agonist activity for the somatostatin type 2 receptor.

A series of 1,6-heptadienes, substituted in the 4 position with nucleic acid bases 1-6, have been synthesized via Mitsunobu condensations. Guanine, adenine, thymine, and uracil derivatives can be prepared directly by coupling the protected base with 1,6-heptadien-4-ol (7). However, coupling protected cytosine and 7 gives an O-alkylated product. Thus, the cytosine derivative must be prepared from the uracil-substituted heptadienes via the triazole. The free-radical addition of CCl(4) and BrCCl(3) to these adducts was investigated. In all cases, both 1:1 and 1:2 adducts were obtained. The 1:1 adduct was identified as the cyclized product of the initially formed 5-hexen-1-yl radical. The cyclization takes place in a stereospecific manner, with only one of the four possible diastereomers resulting. NMR studies indicate that all substituents are cis in this product. In the case of the addition of CCl(4) to the uracil-substituted heptadiene, this conclusion was confirmed by an X-ray structure determination of the isolated cyclized product. The free-radical-initiated cyclocopolymerizations of 1-6 with SO(2) gave 1:1 copolymers with cis-linked five-membered rings. Two-dimensional NMR studies on poly(2-SO(2)) showed predominately the cis-syn isomer while poly(6-SO(2)) has an approximately equal amount of cis-syn and cis-anti isomers.

A variable-temperature (1)H- and (13)C-NMR study revealed a conformational equilibrium for 1,3,3,5,7,7-hexamethyl-1,5-diazacyclooctane (4) having DeltaG() = 8.8 +/- 0.6 kcal/mol at 184 K. This activation barrier connects a major and a minor form of 4. Molecular mechanics calculations on 4 led to the conclusion that the major form is a set of twist-chair-chairs interconverting rapidly via the chair-chair and that the minor form is most likely a set of twist-boat-boats interconverting rapidly via the boat-boat. The proximity of the two nitrogen lone pairs in the major form of 4 made plausible the expectation that 4, as well as a related diamine with apposed nitrogens, 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane (3), might bind a Lewis acid, namely BH(3), using both lone pairs simultaneously and equally. This proved not to be the case: for 3 only the bis-BH(3) adduct was found and for 4 the mono-BH(3) adduct utilized only one nitrogen lone pair. The structure of the bis-BH(3) adduct of 4 (12) was determined by X-ray crystallography to be a twist-boat-boat with BH(3)s cis. Molecular mechanics calculations on 12 were consistent with the solid state conformation found.

Readily available 6-isobutyrylaminopurine can replace either a primary or secondary OH group under Mitsunobu conditions and provide an efficient synthesis of carbocyclic analogs of adenosine. X-ray data indicates that only the desired N9 - substituted derivatives of adenine are formed.

A short synthesis of the title compound (1) from the nucleo-side, 5-amino-4-imidazolecarboxamide riboside (2), is reported, Treatment of 2 with phosphorus oxychloride (POCl3) in trimethyl phosphate...

The first synthesis of 1-(2-deoxy-3-methyl-beta-D-xylosyl)thymine from the unstable 5′-O-trityl-3′-keto-2′-deoxythymidine via a novel organometallic reagent is reported. The stereochemistry at the 3′ position is conclusively determined by chemical means. Some further transformations of the title product are described.

The 31 P{ 1 H} NMR spectra of the monodentate phosphines PMe 2 hex n and PPh 2 Bu n in the presence of Et 4 N [AuBr 2 ] in CDCl 3 solution have been studied at various phosphine/gold ratios and temperatures. At ca. 195 K and a P/Au ratio of 1, only [BrAu(phosphine)] is present. Increasing the amount of phosphine leads to the formation of [BrAu(phosphine) 2 ], [Au(phosphine) 3 ]Br and [Au(phosphine) 4 ]Br. When AuBr 2 − , PMe 2 hex n and PPh 2 Bu n are mixed in a 1:1:1 ratio [BrAu(PMe 2 hex n )], [BrAu(PMe 2 hex n ) 2 ], [BrAu(PPh 2 Bu n )], [BrAu(PPh 2 Bu n ) 2 ] and the mixed ligand [BrAu(PMe 2 hex n )(PPh 2 Bu n )] species are present. Addition of more PMe 2 hex n causes the disappearance of [BrAu(PMe 2 hex n )] with formation of [BrAu(PMe 2− hex n ) 2 ]; however this does not occur in the case of PPh 2 Bu n when [BrAu(PPh 2 Bu n )] is still present even at a Au:PMe 2 hex n :PPh 2 Bu n ratio of 1:1:2. Employing the unsymmetrical ditertiary phosphine Ph 2 P(CH 2 ) 6 PMe 2 enables the identification of the dimeric two- coordinate [BrAu(ligand)AuBr], the dimeric three- coordinate [BrAu(ligand) 2 AuBr] (two forms) and the monomeric three-coordinate [BrAu(ligand)]. Similar studies for the symmetrical ditertiary phosphines Ph 2 P(CH 2 ) 6 PPh 2 (dph) and Me 2 P(CH 2 ) 6 PMe 2 are reported. The rate constants for the exchange BrAu(PMe 2 hex n ) ⇌ BrAu(PMe 2 hex n ) 2 , BrAu(PPh 2 Bu n ) ⇌ BrAu(PPh 2 Bu n ) 2 and BrAu(dph)AuBr ⇌ BrAu(dph) 2 AuBr have been determined from the 31 P{ 1 H} NMR spectra by line shape analysis. Activation parameters have been calculated by a least-squares method. The activation entropies for the exchange processes range from −1.1 to 13.9 cal(mol deg) −1 depending on the ligand type. An associative mechanism is more probable although the possibility of a dissociative process cannot be ruled out. We also report here an improved synthetic method for unsymmetrical bisphosphines with chain length>(CH 2 ) 4 .

We have hypothesized that the biological activity of the antiviral antitumor diterpene aphidicolin requires a specific stereochemical relationship between two rigidly held hydroxyl groups on the alpha face of the molecule. The complex tetracyclic carbon skeleton is not necessary but appears to serve only as a framework on which to hold the hydroxyls. In support of this theory, we have prepared a simple tricyclic triol analogue (7) whose activity approaches that of the natural product in inhibiting in vitro DNA synthesis.