(R)-PFI-2 Analogues as Substrates and Inhibitors of Histone Lysine Methyltransferase SETD7.

(R)-PFI-2 is a histone substrate-competitive inhibitor of the human histone lysine monomethyltransferase SETD7. Aimed at developing potent inhibitors of SETD7 that can also act as small molecule substrates, we replaced the pyrrolidine ring of (R)-PFI-2 with several side chains bearing nucleophilic functional groups. We explored the inhibitory activity of 20 novel (R)-PFI-2 analogues, and found that the most potent analogue has a hydroxyethyl side chain (7).

Examining sterically demanding lysine analogs for histone lysine methyltransferase catalysis.

Methylation of lysine residues in histone proteins is catalyzed by S-adenosylmethionine (SAM)-dependent histone lysine methyltransferases (KMTs), a genuinely important class of epigenetic enzymes of biomedical interest. Here we report synthetic, mass spectrometric, NMR spectroscopic and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics studies on KMT-catalyzed methylation of histone peptides that contain lysine and its sterically demanding analogs. Our synergistic experimental and computational work demonstrates that human KMTs have a capacity to catalyze methylation of slightly bulkier lysine analogs, but lack the activity for analogs that possess larger aromatic side chains.

Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2.

Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like.

Lysine Ethylation by Histone Lysine Methyltransferases.

Biomedicinally important histone lysine methyltransferases (KMTs) catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) cosubstrate to lysine residues in histones and other proteins. Herein, experimental and computational investigations on human KMT-catalyzed ethylation of histone peptides by using S-adenosylethionine (AdoEth) and Se-adenosylselenoethionine (AdoSeEth) cosubstrates are reported. MALDI-TOF MS experiments reveal that, unlike monomethyltransferases SETD7 and SETD8, methyltransferases G9a and G9a-like protein (GLP) do have the capacity to ethylate lysine residues in histone peptides, and that cosubstrates follow the efficiency trend AdoMet>AdoSeEth>AdoEth.

Importance of the main chain of lysine for histone lysine methyltransferase catalysis.

Histone lysine methyltransferases (KMTs) are biomedicinally important class of epigenetic enzymes that catalyse methylation of lysine residues in histones and other proteins. Enzymatic and computational studies on the simplest lysine analogues that possess a modified main chain demonstrate that the lysine's backbone contributes significantly to functional KMT binding and catalysis.

Catalytic Staudinger Reduction at Room Temperature.

We report an efficient catalytic Staudinger reduction at room temperature that enables the preparation of a structurally diverse set of amines from azides in excellent yields. The reaction is based on the use of catalytic amounts of triphenylphosphine as a phosphine source and diphenyldisiloxane as a reducing agent. Our catalytic Staudinger reduction exhibits a high chemoselectivity, as exemplified by reduction of azides over other common functionalities, including nitriles, alkenes, alkynes, esters, and ketones.

Investigating the active site of human trimethyllysine hydroxylase.

The biologically important carnitine biosynthesis pathway in humans proceeds via four enzymatic steps. The first step in carnitine biosynthesis is catalyzed by trimethyllysine hydroxylase (TMLH), a non-heme Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase, which catalyzes the stereospecific hydroxylation of (2)--trimethyllysine to (2,3)-3-hydroxy--trimethyllysine. Here, we report biocatalytic studies on human TMLH and its 19 variants introduced through site-directed mutagenesis.

Model and experimental validation of a unidirectional phase modulator.

A unidirectional phase modulator consisting of tandem phase modulators is studied in detail for use as an integral part of an integrated optical isolator. The effects of non-linearity and residual amplitude modulation in the modulators, as well as the effect of the RF driving signals are captured in a phenomenological model for the first time. The model has been verified experimentally using a device realized in a generic InP based photonic integration platform and is used to study the operating range of the device.

Widely tunable multimode-interference based coupled cavity laser with integrated interferometer.

We present a simple to process tunable laser, fabricated in a low-cost generic fabrication process and based on two coupled Fabry-Perot cavities. The complex coupling coefficients of the coupling element are analytically derived from a 3×3 MMI using coupled mode theory and chosen to maximize the SMSR during lasing operation. Additionally, one of the cavities contains a reflective interferometer, which acts as coarse wavelength selector.

Structure-Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7.

SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs.

Rate-equation theory of a feedback insensitive unidirectional semiconductor ring laser.

For our recently designed continuous-wave and single-frequency ring laser with intra-cavity isolator, we have formulated a rate-equation theory which accounts for two sources of mutual back-scattering between the clockwise and counterclockwise modes, i.e. induced by side-wall irregularities and due to inversion-grating-induced spatial hole burning.

Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II).

Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP.

Poly(methylhydrosiloxane) as a green reducing agent in organophosphorus-catalysed amide bond formation.

Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine.

One-Pot Sulfoxide Synthesis Exploiting a Sulfinyl-Dication Equivalent Generated from a DABSO/Trimethylsilyl Chloride Sequence.

A one-pot process for the synthesis of unsymmetrical sulfoxides using organometallic nucleophiles is described. Sulfur dioxide, delivered from the surrogate DABSO (DABCO-bis(sulfur dioxide)), acts as the initial electrophile and combines with the first organometallic reagent to generate a sulfinate intermediate. In situ conversion of the sulfinate to a sulfinate silyl ester, using TMS-Cl (trimethylsilyl chloride), generates a second electrophile, allowing addition of a second organometallic reagent.

Coupled cavity laser based on anti-resonant imaging via multimode interference.

We report the experimental demonstration of two coupled laser cavities via self-imaging interference in a multimode waveguide. The coupling is optimized by considering images formed by two coherent phase-delayed signals at the input of a 3×3 splitter. As a result, the complex transfer coefficients of the coupling element can be chosen to increase the mode selectivity of the coupled system.

Triphenylphosphine-catalysed amide bond formation between carboxylic acids and amines.

Unactivated carboxylic acids and amines undergo organocatalytic Ph3P/CCl4-mediated amide bond formation by employing in situ reduction of triphenylphosphine oxide to triphenylphosphine in the presence of diethoxymethylsilane and bis(4-nitrophenyl)phosphate.

Rate-equation model for multi-mode semiconductor lasers with spatial hole burning.

We present a set of rate equations for the modal amplitudes and carrier-inversion moments that describe the deterministic multi-mode dynamics of a semiconductor laser due to spatial hole burning. Mutual interactions among the lasing modes, induced by high- frequency modulations of the carrier distribution, are included by carrier-inversion moments for which rate equations are given as well. We derive the Bogatov effect of asymmetric gain suppression in semiconductor lasers and illustrate the potential of the model for a two and three-mode laser by numerical and analytical methods.

Stability of a monolithic integrated filtered-feedback laser.

We experimentally and theoretically investigate the stability of a single-mode integrated filtered-feedback laser as a function of the electrically controlled feedback phase. We interpret the measurements in terms of feedback-induced dynamics, compare them with the results from a stability analysis model for conventional feedback, and find good qualitative agreement.

Saturation-induced frequency shift in the noise spectrum of a birefringent vertical-cavity surface emitting laser.

We show by means of analytical and numerical calculations that saturation, in combination with the linewidth-enhancement factor and the finite rate of spin-flip processes, causes a redshift of the spontaneous-emission peak with respect to the off-lasing-mode frequency in the optical spectrum of a quantum-well vertical-cavity surface emitting laser.

Stability of a diode laser with phase-conjugate feedback.

An exact analysis is presented of the steady-state stability of a semiconductor laser subjected to feedback from a phase-conjugate mirror. Reduced stability occurs at low feedback whenever the effective external delay time is an integer multiple of the relaxation oscillation period. The role of a finite response time of the mirror is to enhance drastically the steady-state stability.

Mode density inside an omnidirectional mirror is heavily directional but not small.

We show that ominidirectional reflection is not a sufficient signature of a photonic bandgap. Although dramatic angular redistribution takes place, the mode density of the electromagnetic field is hardly altered within the ominidirectional reflection range but rather has characteristics typical of a waveguide. The strikingly large polarization anisotropy is due to the huge dielectric contrast but not to a photonic bandgap.

Near fields and far fields generated by sources in the presence of dielectric structures with cylindrical symmetry.

A full-vectorial integral equation method is presented for calculating near fields and far fields generated by sources in the presence of general finite-sized dielectric structures with cylindrical symmetry. The method is relevant for modeling of a class of antenna designs and some optical components with cylindrical symmetry, e.g.

Sudden chaotic transitions in an optically injected semiconductor laser.

We study sudden changes in the chaotic output of an optically injected semiconductor laser. For what is believed to be the first time in this system, we identify bifurcations that cause abrupt changes between different chaotic outputs, or even sudden jumps between chaotic and periodic output. These sudden chaotic transitions involve attractors that exist for large regions in parameter space.

Feedback phase sensitivity of a semiconductor laser subject to filtered optical feedback: experiment and theory.

We investigate experimentally and theoretically the dynamics of a semiconductor laser subject to filtered optical feedback. Depending on the feedback strength we find dynamical regimes with different dependence on the feedback phase. In particular, the influence of the feedback phase on cw emission and on frequency oscillations is characterized experimentally.

New role for nonlinear dynamics and chaos in integrated semiconductor laser technology.

Using an integrated colliding-pulse mode-locked semiconductor laser, we demonstrate the existence of nonlinear dynamics and chaos in photonic integrated circuits (PICs) by demonstrating a period-doubling transition into chaos. Unlike their stand-alone counterparts, the dynamics of PICs are more stable over the lifetime of the system, reproducible from batch to batch and on faster time scales due to the small sizes of PICs.