Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein–ligand–bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.

Enhancement by displacement. A single methyl group displaces a water molecule from the binding site of FKBPs, resulting in the most potent binders known, outperforming the natural products FK506 and rapamycin in biochemical and cellular assays.     

P(SiiPr3)3: the First Trisilylphosphane Derivative with an almost Planar Three‐Coordinated Phosphorus Atom

The title compound ( 1 ) was obtained by salt‐metathesis reaction of iPr₃SiPLi₂ with two molar equiv. of iPr₃SiOTf (OTf = OSO₂CF₃) in 34% yield. Surprisingly, ( 1 ) consists of an 4 : 1 mixture of the two diastereomers ( 1 a ) and ( 1 b ), which do not interconvert to each other even at their decomposition temperature (> 70 °C). They represent different iPr‐rotational isomers which are separated by an unusual high rotational barrier (> 25 kcal mol^–1), resulting from hindered rotations around the Si–C and C–C bonds. The unexpectedly small magnitude of the ¹J(Si, P) coupling constant of ( 1 a ) (9.4 Hz) and ( 1 b ) (9.0 Hz) reflects unusual electronic properties of the Si₃P skeleton. Hitherto only ( 1 a ) could be isolated in the form of single‐crystals and its structure was determined by X‐ray diffraction analysis. The P‐atom in ( 1 a ) is almost planar coordinated (sum of bond angles = 359.789(3)°), but the Si–P‐distance (2.264(7) Å) resembles those values of related silylphosphanes with pyramidally coordinated P atoms. Although MNDO calculations revealed two other iPr‐rotational isomers with similar energy, they prove that the Si₃P skeleton prefers the trigonal‐planar arrangement due to steric congestion.     

The First Orthotelluric Acid Polysilylesters: Synthesis and Crystal Structure of [(Me3SiO)8Te2O2] and [(Me4Si2O2)3Te]

The compounds [(Me₃SiO)₈Te₂O₂] ( 1 ) and [(Me₄Si₂O₂)₃Te] ( 2 ) have been prepared in good yields through Bronsted acid‐base reaction of Te(OH)₆ with Me₃SiNEt₂ and Me₄Si₂(NEt₂)₂, respectively. They have been characterised by multinuclear NMR spectroscopy and single crystal X‐ray diffraction analyses. The formation of dinuclear 1 is the result of fast intermolecular condensation of two partially silylated orthotelluric acid units during the esterification process. Its structure consists of two edge‐fused TeO₆‐octahedra, bearing a four‐membered Te₂O₂ ring as central motif. In contrast, the main structural feature of chiral 2 is a TeO₆ octahedron which is fully silylated by three bidentate 1,1,2,2‐tetramethyldisilanediyl units, resulting in a racemic mixture. The metastability of 2 is remarkable since the Te(+ 6) center usually acts as a strong oxidation reagent toward the Si–Si bond in disilanes. 1 and 2 represent potential starting compounds for molecular Te_xO_y aggregates as hybrid components for new glasses by sol‐gel procedure.     

Ungewöhnliche Reaktivität der Silicium-Phosphor-Doppelbindung in einem Silyliden(fluorsilyl)phosphan: intramolekulare C,H-Inserierung und seine Umwandlung in ein neues Silyliden(silyl)phosphan

Unusual Reactivity of the Silicon-Phosphorus Double Bond in a Silylidene(fluorosilyl)phosphane: Intramolecular C, H Insertion and its Conversion in a New Silylidene(silyl)phosphane Thermolysis of the (fluoro-tert.butyl-2,4,6-triisopropylphenylsilyl)-tert.butyl-2,4,6-triisopropylphenylsilylidenephosphane (“Phosphasilene”) ( 1 ) in toluene at 130 °C leads, under C,H-activation of a methyl group of a ortho-isopropyl group, to the constitutional isomeric silyl(fluorosilyl)phosphane ( 2 ), whose structure has been crystallographically established. It crystallizes racemically and possesses a benzosilacyclopent-2-ene moiety as major structural motif. Lithiation of 2 leads to the corresponding lithium phosphanide ( 3 ), which eliminates LiF at 80 °C in toluene and, concomitantly, furnishes the colorless new silylidene(silyl)phosphane ( 4 ) in the form of its two diasteromers (Z : E ca. 1 : 2). The ³¹P NMR chemical shifts of δ = –29.95 and –31.75 are practically identical with the value of 1 , and the ²⁹Si NMR spectrum shows resonance signals at characteristically low field (δ = 222.5 (¹J(Si, P) = 160 Hz), 221.8 (¹J(Si, P) = 161 Hz)). An single-crystal X-ray diffraction analysis of an enantiomeric form of the E-isomer reveals a Si=P distance of 2.063(2) Å, whereas the Si–P single bond distance of 2.246(2) Å is ca. 8% longer. The low coordinated silicon center is trigonal planar surrounded and the Si–P–Si angle is 108.09(8)°.     

Bis(2‐but­yl‐N,N′‐diisopropyl­amidinato)dichloro­hafnium(IV)

The title compound, [Hf(C₁₁H₂₃N₂)₂Cl₂], is a monomeric hafnium(IV) complex containing two bidentate amidinate ligands and two cis Cl atoms. The crystals are triclinic (space group ) and there is one independent six‐coordinate monomer with a highly distorted octa­hedral geometry in the asymmetric unit. The reported structure is the first hafnium–amidinate complex to be characterized successfully by single‐crystal X‐ray diffraction.     

Synthesis, characterisation and bioimaging of a fluorescent rhenium-containing PNA bioconjugate

A new rhenium tricarbonyl complex of a bis(quinoline)-derived ligand (2-azido-N,N-bis((quinolin-2-yl)methyl)ethanamine, L-N(3)), namely [Re(CO)(3)(L-N(3))]Br was synthesized and characterized in-depth, including by X-ray crystallography. [Re(CO)(3)(L-N(3))]Br exhibits a strong UV absorbance in the range 300-400 nm with a maximum at 322 nm, and upon photoexcitation, shows two distinct emission bands at about 430 and 560 nm in various solvents (water, ethylene glycol). [Re(CO)(3)(L-N(3))]Br could be conjugated, on a solid phase, to a peptide nucleic acid (PNA) oligomer using the copper(I)-catalyzed azide-alkyne cycloaddition reaction (Cu-AAC, "click" chemistry) and an alkyne-containing PNA building block to give Re-PNA. It was demonstrated that upon hybridisation with a complementary DNA strand (DNA), the position of the maxima and emission intensity for the hybrid Re-PNA·DNA remained mainly unchanged compared to those of the single strand Re-PNA. The rhenium-containing PNA oligomer Re-PNA could be then mediated in living cells where they have been shown to be non-toxic contrary to the general notion that organometallic compounds are usually unstable under physiological conditions and/or cytotoxic. Furthermore, Re-PNA could be detected in living cells using fluorescent microscopy.     

Planar chiral (η6-arene)Cr(CO)3 containing carboxylic acid derivatives: synthesis and use in the preparation of organometallic analogues of the antibiotic platensimycin

With more and more organometallic compounds receiving attention for applications in medicinal organometallic chemistry, the need arises for stereoselective syntheses of more complicated structures containing organometallic moieties, for example as isosteric substitutes for organic drug candidates. Herein, the synthesis and characterization of both diastereomers of a planar chiral (η(6)-arene)Cr(CO)(3) containing carboxylic acid derivative, namely, 3-{η(6)-(1, 2, 3, 4-tetrahydro-1-endo/exo-methyl-2-oxonaphthalen-1-yl)-tricarbonylchromium(0)}propanoic acid (7 and 8) is reported. The molecular structures of both were confirmed by single crystal X-ray diffraction. The degree of diastereoselectivity in Cr(CO)(3) complexation with methyl/tert-butyl-3-(1,2,3,4-tetrahydro-1-methyl-2-oxonaphthalen-1-yl)propanoate (4a/4b) vs. the Michael addition of methyl/tert-butyl acrylate to (η(6)-1-methyl-2-tetralone)Cr(CO)(3) (9) was also examined. In the latter case the alkylation was found to be completely diastereoselective and gave methyl/tert-butyl-3-{η(6)-(1, 2, 3, 4-tetrahydro-1-endo-methyl-2-oxonaphthalen-1-yl)-tricarbonylchromium (0)}propanoate (5a and 5b) in excellent yield. Both the carboxylic acids 7 and 8 were coupled with the aminoresorcyclic acid core to achieve diastereomeric bioorganometallics 15a and 15b based on the naturally occurring antibiotic platensimycin lead structure (1a, see Fig. 1). The newly synthesized bioorganometallics were tested against various Gram-positive and Gram-negative bacterial strains but show no promising antibacterial activity.