Publications

The photochemistry of bilirubin has been extensively studied due to its importance in the phototherapy of hyperbilirubinemia. In the present work, we investigated the ultrafast photodynamics of a bilirubin dipyrrinone subunit, vinylneoxanthobilirubic acid methyl ester. The photoisomerization and photocyclization reactions of its (E) and (Z) isomers were studied using femtosecond transient absorption spectroscopy and by multireference electronic structure theory, where the nonadiabatic dynamics was modeled with a Landau–Zener surface hopping technique. The following picture has emerged from the combined theoretical and experimental approach. Upon excitation, dipyrrinone undergoes a very fast vibrational relaxation, followed by an internal conversion on a picosecond time scale. The internal conversion leads either to photoisomerization or regeneration of the starting material. Further relaxation dynamics on the order of tens of picoseconds was observed in the ground state. The nonadiabatic simulations revealed a strong conformational control of the photodynamics. The ultrafast formation of a cyclic photochemical product from a less-populated conformer of the studied subunit was predicted by our calculations. We discuss the relevance of the present finding for the photochemistry of native bilirubin. The work has also pointed to the limits of semiclassical nonadiabatic simulations for simulating longer photochemical processes, probably due to the zero-point leakage issue.

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Phototherapy is a standard treatment for severe neonatal jaundice to remove toxic bilirubin from the blood. Here, the wavelength-dependent photochemistry of vinylneoxanthobilirubic acid methyl ester, a simplified model of a bilirubin dipyrrinone subunit responsible for a lumirubin-like structural rearrangement, was thoroughly investigated by liquid chromatography and mass and absorption spectroscopies, with the application of a multivariate curve resolution analysis method supplemented with quantum chemical calculations. Irradiation of the model chromophore leads to reversible Z → E photoisomerization followed by reversible photocyclization to a seven-membered ring system (formed as a mixture of diastereomers). Both the isomerization processes are efficient (Φ_ZE ∼ Φ_EZ ∼ 0.16) when irradiated in the wavelength range of 360–410 nm, whereas the E-isomer cyclization (Φ_c = 0.006–0.008) and cycloreversion (Φ_–c = 0.002–0.004) reactions are significantly less efficient. The quantum yields of all processes were found to depend strongly on the wavelength of irradiation, especially when lower energy photons were used. Upon irradiation in the tail of the absorption bands (490 nm), both the isomers exhibit more efficient photoisomerization (Φ_ZE ∼ Φ_EZ ∼ 0.30) and cyclization (Φ_c = ∼0.07). In addition, the isomeric bilirubin dipyrrinone subunits were found to possess important antioxidant activities while being substantially less toxic than bilirubin.

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A stereoselective synthesis of the ribosome-binding antitumor antibiotic (−)-bactobolin A is reported. The presented approach makes effective use of (−)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (−)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C–H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (−)-bactobolin A trifluoroacetate in 10% overall yield.

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Synthesis Workshop Video

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Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with focus on the compounds’ potential to be utilized as quality chemical biology probes.

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As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.

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The present invention relates to novel 4-(1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine compounds which are useful in the treatment of lymphomas, leukaemias, and solid tumors.

 

The present invention relates to substituted propanamides as inhibitors of nucleases, especially nuclease MRE11 and MRE11-containing complexes, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as cancer, neurological disorders and other genome instability associated diseases.