The chemistry of 1,1-dibromovinyl functional groups has undergone a renaissance through the application of palladium catalysis. In this study we applied this chemistry to pyrrole derivatives. Thus, this paper focuses on the synthesis of 2 ',2 '-dibromovinyl porphyrins substituted at either the meso- or beta-position of the pyrrole rings directly or through a spacer. Post-functionalization of 2 ',2 '-dibromovinyl porphyrins through organometallic methodologies were studied for cross-coupling reactions using Sonogashira, Suzuki, Heck and Stille conditions and with phosphonates. The assigned structures are supported by HRMS analysis and 1H NMR, 13C NMR and Xray diffraction analysis. The conjugates were investigated for their optical properties. Structural modifications through substitution at different positions of the porphyrin macrocycle and their substitution patterns significantly influence the optical properties of the porphyrins.

We report on the synthesis and spectral properties of BODIPY 1,3-diyne dimers and 1,1-diynyl-1-alkene trimers, prepared via the Pd-catalyzed homocoupling reaction of a series of gem-dibromovinyl BODIPY (1,1-dibromo-1alkene 4,4-difluoro-5-aryl-4-bora-3a,4a-diaza-s-indacene) dyes. The dimer and trimer moieties are connected through the ethynyl bond, attached at p-meso-phenyl or beta-positions of the pyrrole ring, directly or through the phenyl spacer ring at the beta-position. The assigned molecular structures of the products were confirmed using MS, 1H, 13C, 9F NMR and 11B NMR spectroscopic techniques. The absorption, fluorescence and solvatochromic properties were investigated in different solvents. The absorption maxima of unsubstituted pyrrole derivatives are bathochromic shifted as compared to the tetramethyl pyrrole substituted analogs. The highest absorption maxima were obtained when unsubstituted pyrrole 1,1-diynyl-1-alkene trimers featured a phenyl ring at the beta-position. Dimers do fluoresce while trimers are void of fluorescence properties.

A series of versatile phthalocyanine precursors, consisting of gem-dibromovinyl phthalonitrile derivatives, were synthesized and characterized by various spectroscopic techniques. The assigned structures were further supported by X-ray crystallographic techniques. The crystal structures showed primarily C-H & ctdot;N, C-H & ctdot;Br, C-Br & ctdot;N and pi & ctdot;pi interactions. The overall intermolecular interactions in the structures were quantified and fully described by Hirshfeld surface analysis. In addition, energy-frame calculations were used to analyse the three-dimensional topology of the crystal packing. The dispersion energy framework of all compounds was shown to be dominant over the electrostatic framework.

Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in normal dermal fibroblasts, using fluorescence microscopy. The highest level of internalization was observed with 11β-OMe-estradiol-BODIPY 2 and 7α-Me-19-nortestosterone-BODIPY 4 towards cells expressing their specific receptors. Blocking experiments showed changes in non-specific cell uptake in the cancer and normal cells, which likely reflect differences in the lipophilicity of the conjugates. The internalization of the conjugates was shown to be an energy-dependent process that is likely mediated by clathrin- and caveolae-endocytosis. Studies using 2D co-cultures of cancer cells and normal fibroblasts showed that the conjugates are more selective towards cancer cells. Cell viability assays showed that the conjugates are non-toxic for cancer and/or normal cells. Visible light irradiation of cells incubated with estradiol-BODIPYs 1 and 2 and 7α-Me-19-nortestosterone-BODIPY 4 induced cell death, suggesting their potential for use as PDT agents.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The systematic X-ray structure analyses of the primary cholesterol sidechain autoxidation products cholesterol 25- and 20β(S)-hydroperoxide are presented and compared to cholesterol and 25-hydroxycholesterol. Intermolecular interactions in crystal structures of the molecules are revealed through Hirshfeld surface analysis and fingerprint plots. The magnitude of energy frameworks is presented by combining efficient calculations of intermolecular interaction energies with novel graphical representation.

The chemistry of gem-dibromovinyl derivatives has undergone a renaissance through the application of palladium catalysis and has been applied to pyrrole substituted gem-dibromovinyl BODIPY. gem-Dibromovinyl BODIPYs (substituted at either the [Formula: see text]-position of 8-phenyl or the [Formula: see text]-position of the pyrrole rings) were studied for cross-coupling reactions using Sonogashira, Suzuki, Heck and Stille conditions, and with phosphonates and thiols. The assigned structures were supported by MS and 1H NMR, [Formula: see text]C NMR, X-ray diffraction analysis as well as optical spectroscopy. The conjugates were investigated for their absorption, fluorescence and solvatochromic properties in different solvents. Substitution at the [Formula: see text]-position of 8-phenyl derivatives of gem-diethynyl BODIPYs did not induce any shift in the absorption maximum, while the [Formula: see text]-position pyrrole substituted derivatives showed a red shift. Aromatic compounds gave larger red shifts as compared to the aliphatic substituted analogs.

The Front Cover shows the methodology for the synthesis of diversified "Y-enyene" BODIPY derivatives, obtained through the Pd-catalyzed Sonogashira coupling reaction of gem-dibromo BODIPY and alkyne derivatives. The coupling products possess interesting spectral properties (UV/Vis and fluorescence), providing the potential to develop fluorescence probes and photosensitizers for photodynamic therapy (PDT). Protonation of dimethylaminphenyl substituted BODIPYs induces changes in their spectral properties, from fluorescence off-to-on. Their strong electrochromic properties render these derivatives most suitable for the construction of multifunctional electro- and photo-chemical molecular switches. More information can be found in the Full Paper by J. E. van Lier et al.

The photodynamic properties of phthalocyanines (Pc) and their potential as second-generation photosensitizers for the photodynamic therapy of cancer has been reviewed on several occasions. This chapter reviews the basic structural requirements of Pc to function as efficient photosensitizers in the photodegradation of biomolecular targets. Water-soluble sulfonated metallophthalocyanines (M-PcS) tend to form pho-tochemically inactive aggregates that do not fluoresce and are characterized by a broadening and a 30 to 50-nm blue shift of the Q-band. The same dynamics between M-PcS and plasma proteins that facilitate their transport to the interstitial tumor space likely play a role in the dye uptake by neoplastic cells. The variations in the potential to inflict direct tumor cell kill are surprisingly small for M-PcS that are sulfonated to different degrees, particularly in considering the distinct differences in their intratumoral distribution pattern.

A series of BODIPYs (boron-dipyrromethene dyes; 4,4-difluoro-5-aryl-4-bora-3a,4a-diaza-s-indacene) derivatives, bearing an aldehyde group at different pyrrole positions, were transformed into gem-dibromovinyl analogs using the Corey-Fuchs or Lautens olefination method. The gem-dibromovinyl moieties (one or two) are symmetric/asymmetric and attached at α- or β-positions of the pyrrole ring, directly or through the extension of a β-position substituted phenyl spacer ring. The molecular structures of the resultant dyes were assigned using MS, 1H, 13C, 19F NMR, X-ray diffraction and for some compounds 2D HSQC and 11B NMR. The absorption, fluorescence and solvatochromism properties were investigated in different solvents. The highest absorption and emission maxima were obtained for compounds having two gem-dibromovinyl groups attached directly at the α-positions. The best correlation (R-coefficient) of absorption between the solvents and spectral properties of the BODIPYs was obtained using the refractive index of the solvent. The R-coefficient of emission was obtained only for compounds having gem-dibromo vinyl moieties at α-positions. Their solid states clearly reveal distinct patterns of gem-dibromovinyl orientation, torsion angles of the 5-phenyl ring and the indacene plane. Hirshfeld surface analyses were used to visualize various intermolecular interactions.

A family of new asymmetric and symmetric 1,3,7,9-tetramethyl-4,4-bora difluoro-diaza-s-indacene (BODIPY) derivatives, bearing gem-dibromovinyl substituents, was synthesized by the Corey-Fuchs olefination method. One or two gem-dibromovinyl moieties were attached at either the p-position of 5-phenyl, or the β-position of the pyrrole ring, directly or, through phenyl spacers. The assigned structures were supported by MS, NMR (1H, 13C, 19F), X-ray diffraction analysis and for some compounds 2D HSQC and 11B NMR as well as optical spectroscopy. Their absorption and fluorescence properties and solvatochromism in different solvents were investigated. The highest absorption and emission maxima were obtained for compounds having two gem-dibromovinyl groups attached directly or through the phenyl spacer. The best correlation (R-coefficient) between the solvent and spectral properties of the BODIPYs were obtained using the refractive index of the solvent. Although these compounds are structurally quite similar, their solid states show remarkable differences in the crystal system, clearly revealing two distinct patterns of gem-dibromovinyl orientation and torsion angles of the 5-phenyl ring and the indacene plane. Hirshfeld surface analysis data were used to visualize various intermolecular interactions.

Cytochrome P450 46A1 (CYP46A1) or cholesterol-24-hydroxylase is responsible for cholesterol metabolism and homeostasis in the human brain. More recently its activity has been linked to brain function and disease. The anti-HIV drug efavirenz activates CYP46A1 at low drug levels while inhibiting the enzyme activity at the high dose used in clinical practice. Synthetic analogs and hydroxylated metabolites of efavirenz enhance CYP46A1 activity, with reduced unwanted enzyme inhibition at higher concentrations. These observations provide a platform for structural modifications of efavirenz to modulate CYP46A1 activity as a therapeutic target of brain disorders such as Alzheimer's disease, for which currently no treatment is available.

Fluorescence and SPECT/PET imaging are powerful tools currently in use by the scientific community and receiving a great attention for the development of dual-modality imaging agents. BODIPYs are among the most promising candidates to be used for such functions due their excellent absorbance and fluorescence properties as well as their ease of radiolabeling without compromising their biological properties. In this manuscript we present an overview of BODIPY radiolabeling methods and their relevance to the development of multimodality agents.

After encouraging preclinical and human dosimetry results for the novel estrogen receptor (ER) PET radiotracer 4-fluoro-11β-methoxy-16α-18F-fluoroestradiol (18F-4FMFES), a phase II clinical trial was initiated to compare the PET imaging diagnostic potential of 18F-4FMFES with that of 16α-18F-fluoroestradiol (18F-FES) in ER-positive (ER+) breast cancer patients. Methods: Patients diagnosed with ER+ breast cancer (n = 31) were recruited for this study, including 6 who underwent mastectomy or axillary node dissection. For each patient, 18F-FES and 18F-4FMFES PET/CT scans were done sequentially (within a week) and in random order. One hour after injection of either radiotracer, a head-to-thigh static scan with a 2-min acquisition per bed position was obtained. Blood samples were taken at different times after injection to assess each tracer metabolism by reverse-phase thin-layer chromatography. The SUVmean of nonspecific tissues and the SUVmax of the tumor were evaluated for each detected lesion, and tumor-to-nonspecific organ ratios were calculated. Results: Blood metabolite analysis 60 min after injection of the tracer showed a 2.5-fold increase in metabolic stability of 18F-4FMFES over 18F-FES. Although for most foci 18F-4FMFES PET had an SUVmax similar to that of 18F-FES PET, tumor contrast improved substantially in all cases. Lower uptake was consistently observed in nonspecific tissues for 18F-4FMFES, notably a 4-fold decrease in blood-pool activity as compared with 18F-FES. Consequently, image quality was considerably improved using 18F-4FMFES, with lower overall background activity. As a result, 18F-4FMFES successfully identified 9 more lesions than 18F-FES. Conclusion: This phase II study with ER+ breast cancer patients showed that 18F-4FMFES PET achieves a lower nonspecific signal and better tumor contrast than 18F-FES PET, resulting in improved diagnostic confidence and lower false-negative diagnoses.

This review focuses on progress in the development of different approaches to the design of steroid ([Formula: see text] estrogens, androgens, cholesterol) conjugates with coordination assemblies of metalloporphyrins, phthalocyanines and related complexes. Porphyrins and phthalocyanines have received considerable attention due to their novel composition, intriguing spectroscopic, photophysical, and redox properties, and potential application in light-harvesting and optoelectronic devices. With the development of more efficient imaging and therapeutic applications, these bio-conjugates are evaluated as multimodality agents (PET, fluorescence imaging) to monitor the mechanism of action of biologically active components in living systems and as agents for molecular recognition, oxygen atom transfer and catalysis. The tetrapyrrole components, which can be coupled via covalent and various non-covalent linkages, may exhibit strong interactions through efficient photo-induced electron and/or energy transfer processes.