Abstract. A comprehensive crystallographic analysis of 10 porphyrin quinone precursors (dimethoxybenzene derivatives), and six porphyrin quinones has been performed. The free bases and zinc(II) complexes of the porphyrin quinones are of the 5,10,15‐triaryl/alkyl‐20‐quinone‐porphyrin type and carry various bridging and quinone units. The structural and conformational parameters were determined for all compounds; the donor‐acceptor separation distances range from 6.3 to 10.9 Å. Knowledge of these data is a prerequisite for a detailed interpretation of theoretical and spectroscopic studies on such systems. Despite the obvious influence of the type and geometry of the bridging unit and quinone on the spatial arrangement of the donor and acceptor components, a large variety of different packing arrangements in the crystal were observed. These include π stacking, aggregate formation and axial ligation in the zinc(II) porphyrins. The latter often utilized the quinone (or dimethoxy) oxygen atoms for coordination to zinc(II) centers leading to porphyrin quinone dimers and even polymers.

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Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are not commonly used in clinical practice for treatment of B‐cell lymphomas, although a subset of patients with refractory or relapsed B‐cell lymphoma achieved partial or complete remissions. Therefore, the purpose of this study was to identify molecular features that predict the response of B‐cell lymphomas to SAHA treatment. We designed an integrative approach combining drug efficacy testing with exome and captured target analysis (DETECT). In this study, we tested SAHA sensitivity in 26 B‐cell lymphoma cell lines and determined SAHA‐interacting proteins in SAHA resistant and sensitive cell lines employing a SAHA capture compound (CC) and mass spectrometry (CCMS). In addition, we performed exome mutation analysis. Candidate validation was done by expression analysis and knock‐out experiments. An integrated network analysis revealed that the Src tyrosine kinase Gardner‐Rasheed feline sarcoma viral (v‐fgr) oncogene homolog (FGR) is associated with SAHA resistance. FGR was specifically captured by the SAHA‐CC in resistant cells. In line with this observation, we found that FGR expression was significantly higher in SAHA resistant cell lines. As functional proof, CRISPR/Cas9 mediated FGR knock‐out in resistant cells increased SAHA sensitivity. In silico analysis of B‐cell lymphoma samples (n = 1200) showed a wide range of FGR expression indicating that FGR expression might help to stratify patients, which clinically benefit from SAHA therapy. In conclusion, our comprehensive analysis of SAHA‐interacting proteins highlights FGR as a factor involved in SAHA resistance in B‐cell lymphoma.

Rigidly and covalently linked porphyrin quinones are well-suited as biomimetic model compounds for studying the photoinduced electron transfer (PET) reaction occurring in primary processes of photosynthesis. In this context, the synthesis of new porphyrin quinones with a cis- or trans-1,4-disubstituted cyclohexylene bridge linking the electron donor and the electron acceptor is reported. To study the dependence of the PET rate of the difference of the free enthalpy of the PET reaction, four quinones with different structures and therefore redox potentials were used as electron acceptor components. As a whole, two series of each four new cis- and trans-1,4-cyclohexylene-bridged porphyrin quinones with variable acceptor strength were synthesized. The most important synthetic steps comprised the free radical addition of the ester functionalized cyclohexylene bridge to the quinone, reduction of the ester to the alcohol group with lithium borohydride or DIBALH, oxidation of the alcohol to the corresponding aldehyde with PCC or TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)/NaOCl, and condensation of these aldehydes with pyrrole and 4-methylbenzaldehyde under equilibrium conditions. Analysis of the 1H NMR spectra unambiguously indicated the chair conformation for the cyclohexane ring of all porphyrin precursors and trans-cyclohexane-bridged porphyrin quinones, whereas the cis-cyclohexane-bridged porphyrin quinones had the cyclohexane ring in the unusual twist-boat conformation. This was additionally confirmed by an X-ray crystal structure of one of the cis-porphyrin quinones and the corresponding trans-porphyrin quinone. NOE experiments gave information about the spatial arrangement of the diastereomeric target compounds in solution.

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