Novel androgen receptor full antagonists: Design,synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p-carborane cages

Based on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of 6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6c is in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity.     

The synthesis and structural characterization of carborane oligomers connected by carbon-carbon and carbon-boron bonds between icosahedra

The reaction of dilithiated o-carborane (closo-1,2-Li₂-1,2-C₂B₁₀H₁₀) with CuCl₂ gives 1,1′-bis(o-carborane) (1), 1,3′-bis(o-carborane) (2) and 1,4′-bis(o-carborane) (3). Compound 2 (C₄B₂₀H₂₂) crystallizes in the monoclinic space group P2₁/n with A = 6.9275(6), B = 9.7655(8), C = 12.356(1) Å, β = 90.028(2)° and Z = 2. The structure was solved by direct methods and refined to R = 0.048 and R_w = 0.074. Compound 3 (C₄B₂₀H₂₂) crystallizes in the orthorhombic space group P2₁2₁2₁ with A = 6.8854(5), B = 12.523(1), C = 19.847(1) Å and Z = 4. The structure was solved by direct methods and refined to R = 0.078 and R_w = 0.091. The coupling reaction of dilithiated m-carborane (closo-1,7-Li₂-1,7-C₂B₁₀H₁₀) with CuCl₂ results in the formation of 1,1′-bis(m-carborane) (4) and tetra(m-carborane) (5).     

Novel polynuclear thallium thiolates with cage structures

Yellow thallium(I)-tetra(2-butanethiolato)-thallium(III) Tl[Tl(SC₄H₉)₄] (1) crystallizes from a solution of thallium(I) carbonate and 2-butanethiol in DMF after heating under reflux in air. In the crystal structure (space group: , a = 8.941(3) Å, b = 11.078(4) Å, c = 13.458(4) Å, α = 70.81(3)°, β = 83.65(3)°, γ = 74.78(3)°, Z = 2) regular, TlS₄ tetrahedra are bridged by thallium(I) atoms to an one-dimensional framework. The thallium(I) atoms are in fivefold distorted coordination and are linked to four further TlS₄ tetrahedra. The resulting Tl₄(S-Bu)₈ units consist of two face-sharing Tl₃S₄ defect cubane entities.TlSC₃H₇ (2) was obtained from a solution of thallium(I) carbonate and 2-propanethiol in DMF after heating under reflux in air. The crystal structure (space group C2/c, a = 22.501(5) Å, b = 10.360(2) Å, c = 12.760(3) Å, β = 107.92(2)°, Z = 16) contains novel [Tl₄(SPr)₅]⁻ units which are linked via thallium atoms to one-dimensional molecular chains running parallel to [0 0 1].     

Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III

Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is a zinc-hydrolase with an indicated role in the mammalian pain modulatory system. In order to find a potent antagonist of this enzyme, we synthesized and screened the effect of a small set of benzimidazole derivatives on its activity. To improve the inhibitory potential, a cyclobutane ring was introduced as rigid conformation support to the diamidino substituted dibenzimidazoles. Two such compounds (1' and 4') from the group of cyclobutane derivatives containing amidino-substituted benzimidazole moieties, obtained by photochemical cyclization in water and by respecting rules of the "green chemistry" approach, were found to be strong DPP III inhibitors, with IC(50) value below 5 microM. Compound 1' displayed time-dependent inhibition towards human DPP III, characterized by the second-order rate constant of 6924+/-549 M(-1)min(-1) (K(i)=0.20 microM). The peptide substrate valorphin protected the enzyme from inactivation by 1'.     

Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators

This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow.     

Ketimine synthesis in the coordination sphere of thallium (I)

[AuTl(C₆F₅)₂(en)] (en = ethylenediamine) reacts with cyclic ketones as cyclopentanone (Cy⁵O), cyclohexanone (Cy⁶O) or cycloheptanone (Cy⁷O) in 1:1 or 1:2 molar ratio leading to products of stoichiometry [AuTl(C₆F₅)₂{Cy^xN(CH₂)₂NH₂}] (x = 5 1, 6 2 or 7 3), or [AuTl(C₆F₅)₂{Cy^xN(CH₂)₂NCy^x}] (x = 5 4, 6 5 or 7 6). Addition of ethylenediamine to the ketimine complexes in chloroform regenerates [AuTl(C₆F₅)₂(en)], the starting material, and the free ketimines, as their NMR and mass spectra evidenced. The ketimine complexes display luminescence in solid state at room temperature and at 77 K at higher wavelengths than the diamine starting product (505 nm). The excited states responsible for this behaviour are assigned to orbitals due to the gold-thallium interactions.     

Porosity tuning of carborane-based metal-organic frameworks (MOFs) via coordination chemistry and ligand design

Two new metal-organic framework (MOF) materials based on boron-rich cluster struts (p-carborane) are reported herein. Cu(I) catalyzed coupling chemistry was used to synthesize carboxylate-based ligands, which are substantially longer than the previously studied dicarboxylated p-carborane, leading to structures with greater porosity. Solvothermal syntheses involving these ligands and Zn salts were used to prepare two new Zn(II)-based MOFs with 2D and 3D open framework structures. Upon thermal activation, these MOFs retain the chemical identity of their frameworks, leading to highly porous materials.     

Novel bis(diethylenetriamine)thallium(III) complex. Synthesis and characterization in pyridine solution and in solid

A new complex of thallium(III) with the nitrogen donor ligand diethylenetriamine (dien) has been prepared and characterized by multinuclear NMR (¹H, ¹³C, ²⁰⁵Tl), infrared and Raman spectroscopy, and X-ray diffraction. In solution, the symmetric s-facial isomer of [Tl(dien)₂]³⁺ is formed. This is a fluxional molecule even at low temperature (235 K); therefore, the different rotamers cannot be observed separately. A complete characterization of the complex is given from its non-trivial NMR spectra. The crystal structure of [Tl(dien)₂](ClO₄)₃·H₂O shows u-facial geometry, where the coordination environment around thallium can be described as a distorted trigonal prism.     

Novel N-3 substituted TSAO-T derivatives: synthesis and anti-HIV-evaluation

Novel derivatives of the anti-HIV-1 agent, TSAO-T, bearing at the N-3 position alkylating groups or photoaffinity labels were prepared and evaluated for their anti-HIV activity. All of these compounds demonstrated pronounced anti-HIV-1 activity and inhibited HIV-1 RT; however, we were unable to detect stable covalent linkages between inhibitor and enzyme. In addition, compounds with an alcohol functional group connected to the N-3 position through a cis or trans double bond have been prepared. These compounds have been useful to study how the conformational restriction of the linker affects in the interaction between the N-3 substituent and the HIV-1 RT enzyme.     

Modular synthesis of new C-aryl-nucleosides and their anti-CML activity

The C-aryl-ribosyles are of utmost interest for the development of antiviral and anticancer agents. Even if several synthetic pathways have been disclosed for the preparation of these nucleosides, a direct, few steps and modular approaches are still lacking. In line with our previous efforts, we report herein a one step - eco-friendly β-ribosylation of aryles and heteroaryles through a direct Friedel-Craft ribosylation mediated by bismuth triflate, Bi(OTf)₃. The resulting carbohydrates have been functionalized by cross-coupling reactions, leading to a series of new C-aryl-nucleosides (32 compounds). Among them, we observed that 5d exerts promising anti-proliferative effects against two human Chronic Myeloid Leukemia (CML) cell lines, both sensitive (K562-S) or resistant (K562-R) to imatinib, the “gold standard of care” used in this pathology. Moreover, we demonstrated that 5d kills CML cells by a non-conventional mechanism of cell death.     

Novel synthesis of zymosterol

A modified scheme for the synthesis of zymosterol, one of the biosynthetically important yeast sterols, starting from from 3-benzoyloxyergosta-8(14),22-dien-15-one has been suggested.     

Synthesis and isocyanate insertion reactions of tungsten(IV) imido complexes formed from W(CO)(acac)(N3)(PMe3)3 with azide as the oxidant

Addition of excess trimethylphosphine and a halide source to a solution of W(CO)(acac)₂(η²-L) (L = NCPh and OCMe₂) leads to displacement of L and one acetylacetonate chelate to produce electron-rich, seven-coordinate complexes of the formula W(CO)(acac)(X)(PMe₃)₃ (X = Cl, Br, and I). Use of NaN₃ instead of a halide source leads primarily to loss of carbon monoxide and dinitrogen, and protonation from adventitious water yields the cationic imido complex [W(NH)(acac)(PMe₃)₃]⁺. Heating [W(NH)(acac)(PMe₃)₃]⁺ in aromatic isocyanates at high temperature results in isocyanate insertion into the NH imido bond to form new C-N bonds. An alternate route to related imido complexes involves heating [W(O)(acac)(PMe₃)₃]⁺ with phenyl isocyanate at high temperatures to yield the substituted imido complex [W(NPh)(acac)(PMe₃)₃]⁺.     

Novel porphyrin-thallium-platinum complex with “naked” metal-metal bond: multinuclear NMR characterization of [(tpp)Tl-Pt(CN)5] and [(thpp)Tl-Pt(CN)5] in solution

The novel porphyrin-thallium-platinum complexes with “naked” metal-metal bond, with the composition [(tpp)Tl-Pt(CN)₅]²⁻ (1) and [(thpp)Tl-Pt(CN)₅]²⁻ (2) (tpp = tetraphenylporphrin and thpp = tetrakis(4-hydroxyphenyl)-porphine), were synthesized and characterised by multinuclear NMR (²⁰⁵Tl, ¹⁹⁵Pt, ¹³C and ¹H) and Raman spectroscopies in solution. The presence of a direct Pt-Tl metal-metal bond in the complexes is convincingly confirmed by a very strong one-bond ¹⁹⁵Pt-²⁰⁵Tl spin-spin coupling (47.8 and 48.3 kHz for 1 and 2, respectively) detected in both Pt and Tl NMR spectra. The corresponding force constant in molecule 1, 1.92 N cm⁻¹, was calculated using Raman stretching frequency of the Pt-Tl vibration and is characteristic for a single metal-metal bond.     

Water-controlled reactions selectivity of the ReOCl3(OPPh3)(SMe2) synthon with a hydrophosphorane ligand

The reaction of the hydrospirophosphorane HP(OCMe₂CMe₂O)₂ ligand or the five-membered cyclic hydrogen phosphonate HP(O)(OCMe₂CMe₂O) ligand with the ReOCl₃(OPPh₃)(SMe₂) precursor under controlled reaction conditions led to the isolation of dimeric oxo-rhenium(V) complexes containing P(O)(OCMe₂CMe₂O)⁻ moieties, represented by [ReOCl₂{μ-OP(OCMe₂CMe₂O)}₃ReOCl(OPPh₃)] (1) and [ReOCl₂(SMe₂){μ-OP(OCMe₂CMe₂O)}]₂ (2). The chemical composition of these complexes was established by means of NMR, IR spectroscopic methods, and based on analytical data. The relative stereochemistry of 1 and 2 was unambiguously determined by single X-ray diffraction studies. The crystal structure of 1 comprises two crystallographically independent molecules in an asymmetric unit and co-crystallised molecules of both dichloromethane and acetonitrile. Two different six-coordinated monomeric subunits, ReOCl₂ and ReOCl(OPPh₃), connected by three phosphonate bridges, build up the dinuclear complex 1. It exhibits an uncommon feature, a cis disposition of the triphenylphosphine oxide molecule relative to the terminal ReO bond. The crystal structure of 2 includes four molecules, in which two equivalent rhenium subunits ReOCl₂(SMe₂) are linked by two P(O)(OCMe₂CMe₂O)⁻ bridges.     

Starch vermicelli template-assisted synthesis of size/shape-controlled nanoparticles

Size- and shape-controlled syntheses of silver and gold nanoparticles have been successfully developed using partially hydrolyzed starch vermicelli templates as green nanoreactors for the growth of nanoparticles. Mung bean vermicelli is of interest due to the higher amylose content and its transparency, allowing the formation of coloured particles on the vermicelli to be observed. The as-prepared silver and gold nanoparticles were characterized by UV–Visible spectroscopy, transmission electron microscopy (TEM), and X-ray diffraction (XRD). The carbonization of as-prepared vermicelli at 200 °C, 300 °C, and 500 °C was carried out to investigate nanoparticles embedded in the starch vermicelli templates. TEM of carbonized samples revealed the interesting patterns of gold nanorods and silver nanowire-liked assemblies along with carbon nanotubes. The carbonization of silver nanoparticles at 500 °C resulted to the loss of starch vermicelli capping nanoparticles and this led to the higher diffusion rate of nanoparticles to generate silver nanodendrites on TEM images. XRD data of carbonized yellow and purple silver nanoparticles revealed the presence of silver nanoparticles and a mixture of silver and silver chloride nanoparticles, respectively. This approach offers a great potential to design new fine structures of vermicelli and utilize its structure as a template for the large-scale synthesis of size- and shape-controlled silver and gold nanoparticles for chemical and biological applications.     

Novel synthesis of 2'-O-methylguanosine

An efficient and chemoselective synthesis of 2'-O-methylguanosine (6) has been accomplished in high yield without protection of the guanine base. The salient feature of the synthesis of 6 lies in the application of methylene-bis-(diisopropylsilyl chloride), (MDPSCl(2), 2) as a new 3',5'-O-protecting group for nucleosides. Use of CH(3)Cl as a weak electrophile and NaHMDS as a mild base was crucial to the success of the 2'-O-methylation of 3',5'-O-protected guanosine.     

Aqueous acid-base chemistry involving dioxovanadium(V) complexes of 2,6-pyridinedimethanol, and the X-ray structures of Na[VO2{2,6-(OCH2)2NC5H3}] · 4H2O and [1-H-2,6-(HOCH2)2NC5H3]Cl

Reaction of NH₄VO₃ with 2,6-pyridinedimethanol in water at 85 °C followed by the room temperature addition of HCl (aq) yields [HVO₂(pydim)]_x (pydim = 2,6-pyridinedimethanolato dianion), as a sparingly soluble off-white solid. This acid may be deprotonated by titration with NaOH (aq), yielding Na[VO₂(pydim)] · 4H₂O, which has been structurally characterized by single-crystal X-ray diffraction. Treating Na[VO₂(pydim)] · 4H₂O with HCl (aq) regenerates [HVO₂(pydim)]_x, but reaction with additional NaOH (aq) displaces the pyridinedimethanolato ligand from the vanadium center. Similarly, treating [HVO₂(pydim)]_x with excess HCl (aq) strips the pyridinedimethanolato ligand from the vanadium center and yields the adduct [H₃(pydim)]⁺Cl⁻ as one component in a mixture of products. This adduct has been structurally characterized by single-crystal X-ray diffraction. The optimum pH range for stable dioxovanadium(V) complexes stabilized by the 2,6-pyridinedimethanolato ligand is at least 1.5-9.4.     

Novel 3-methylindoline inhibitors of EZH2: Design,synthesis and SAR

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.     

Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity

A series of pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives 6, 7a-c, 8a,b, 9a,b and 10-12 were synthesized as modified pyrazoloquinolinone analogs (PQs) and evaluated for their ability to inhibit radioligand to central and peripheral benzodiazepine receptors (BZRs) and their effect on GABA(A) alpha1beta2gamma2L receptors expressed in Xenopus laevis oocytes. Multistep synthesis starting from 5-nitroindole, via the Gould-Jacobs reaction to the quinoline nucleus, yielded key intermediates 9-chloro-3H-pyrrolo[3,2-f]quinoline-8-carboxylates. The reaction of the latter with methyl-hydrazine and various phenyl-hydrazines furnished the final compounds. In order to confirm the expected tetracyclic 2-substituted-2H-pyrazolopyrroloquinolin-3-one structure, IR spectrophotometric, mono-1H and 13C and bi-dimensional spectrometric and HRMS analyses were carried out: all compounds were found to be 2-substituted 3-keto tautomers; compound 6 only differed because it turned out to be 1-methyl-2H-pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-olo. The results of this work are consistent with those previously reported for PQs: 7-9 show high potency in displacing specific [3H]flunitrazepam from its receptor site; no compound was active in inhibiting the binding of [3H]PK 11195. They all act as antagonists at central BZR.