Regina Czerwonka

Synthesis and activity of carbazole derivatives against Mycobacterium tuberculosis

Infecting one-third of the world’s inhabitants, Mycobacterium tuberculosis (MTB) is deemed a serious public health concern. Failure to follow the current regimen along with the HIV pandemic have led to the emergence of multiple drug-resistant tuberculosis (MDR-TB) strains. The pursuit of more efficacious drugs and prophylaxis is warranted. Findings of some naturally occurring carbazole alkaloids (Figure 1), exhibiting antituberculosis activity, have prompted us to explore further carbazole derivatives for structure–activity relationships. Clausine K or clauszoline J, a natural product isolated independently from several sources, was found to have weak antituberculosis activity (MIC of 100 mgmL 1 against the H37Ra strain). Ma et al. isolated micromeline from the stem bark of Micromelum hirsutum along with some known carbazole alkaloids, and found the MIC to be 31.5 mgmL 1 against M. tuberculosis H37Rv (selectivity index >3). [8] Based on these findings, we screened a series of carbazole alkaloids and derivatives for their in vitro anti-TB activity to find out whether the carbazole framework represents a novel antituberculosis scaffold. The intention of the present study was to identify potent anti-TB active carbazoles and to establish preliminary structure–activity relationships (SAR). Compounds 4a–i were purchased from Sigma Aldrich; 4 j–v and 8–15 were prepared using either the iron-mediated or the palladium-catalyzed approach previously developed by our group (Schemes 1 and 2, Table 1). An electrophilic aromatic substitution of the tricarbonyliron-cyclohexadienylium salts 1 and the arylamines 2 affords functionalized tricarbonyliron complexes 3. The oxidative cyclization of the tricarbonyliron complexes 3 furnishes substituted carbazole derivatives 4. In another approach, the palladium(0)-catalyzed amination of aryl

Transition metals in organic synthesis - Part 83#: Synthesis and pharmacological potential of carbazoles

A series of carbazole derivatives with promising pharmacological properties has been prepared using either an iron-mediated or a palladium-catalyzed synthetic approach. The carbazole alkaloids carbazoquinocin C, carbazomadurin A and B, epocarbazolin A and B, neocarazostatin B, and carquinostatin A are antioxidants acting as free-radical scavengers. Thus, they represent potential lead compounds for the development of novel drugs against diseases initiated by oxygen-derived free radicals. Initiated by the first naturally occurring carbazole alkaloids with antituberculosis (anti-TB) activity, clausine K and micromeline, a study on the structure–activity relationships for anti-TB-active carbazole derivatives has been carried out. The 6-oxygenated carbazoles glycozoline and glycozolinine show antibiotic activity towards several microorganisms. The 7-oxygenated carbazole siamenol exhibits anti-HIV activity.

Snapshot of the palladium(II)-catalyzed oxidative biaryl bond formation by X-ray analysis of the intermediate diaryl palladium(II) complex.

Pd(II) caught in the act: The diaryl Pd(II) intermediate of a Pd(II)-catalyzed oxidative biaryl bond formation proceeding via a double C-H bond activation has been isolated and fully characterized, including an X-ray crystal structure analysis. Stabilization due to chelation by adjacent pivaloyloxy and acetyl groups has allowed the isolation of this long-sought crucial intermediate. On gentle warming, the complex is transformed into a carbazole product, and the catalytically active Pd(II) species is regenerated by oxidation with Cu(II).

Optimisation, Scope and Limitations of Enantioselective Aldol Reactions of an S‐Ketene Silyl Acetal with Aliphatic Aldehydes under (R)‐BINOL‐Titanium(IV) Catalysis Conditions

The Mukaiyama aldol reaction between the functionalised aldehydes 5 and the S-ketene silyl acetal 2 catalysed by 1,1′-binaphthyl-derived chiral titanium(IV) complex 4 afforded the corresponding aldol products 6 in good yields and with good to excellent enantioselectivities. The chemical yield could further be enhanced, without loss of stereoselection, by addition of phenol and/or molecular sieves. The presented aldol reactions with aluminium, boron and ytterbium-BINOL catalysts demonstrate that only low chiral induction can be achieved. Aldol product 6a was converted into an α-lipoic acid precursor 8, thus providing a formal synthesis of this biologically active compound. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

ON THE RELEVANCE OF POLYYNYL-SUBSTITUTED POLYCYCLIC AROMATIC HYDROCARBONS TO ASTROPHYSICS

We report on the absorption spectra of the polycyclic aromatic hydrocarbon (PAH) molecules anthracene, phenanthrene, and pyrene carrying either an ethynyl (-C2H) or a butadiynyl (-C4H) group. Measurements were carried out in the mid infrared at room temperature on grains embedded in CsI pellets and in the near ultraviolet at cryogenic temperature on molecules isolated in Ne matrices. The infrared measurements show that interstellar populations of polyynyl-substituted PAHs would give rise to collective features in the same way non-substituted PAHs give rise to the aromatic infrared bands. The main features characteristic of the substituted molecules correspond to the acetylenic CH stretching mode near 3.05 mum and to the almost isoenergetic acetylenic CCH in- and out-of-plane bending modes near 15.9 mum. Sub-populations defined by the length of the polyynyl side group cause collective features which correspond to the various acetylenic CC stretching modes. The ultraviolet spectra reveal that the addition of an ethynyl group to a non-substituted PAH molecule results in all its electronic transitions being redshifted. Due to fast internal energy conversion, the bands at shorter wavelengths are significantly broadened. Those at longer wavelengths are only barely affected in this respect. As a consequence, their relative peak absorption increases. The substitution with the longer butadiynyl chain causes the same effects with a larger magnitude, resulting in the spectra to show a prominent if not dominating pi-pi* transition at long wavelength. After discussing the relevance of polyynyl-substituted PAHs to astrophysics, we conclude that this class of highly conjugated, unsaturated molecules are valid candidates for the carriers of the diffuse interstellar bands.We report on the absorption spectra of the polycyclic aromatic hydrocarbon (PAH) molecules anthracene, phenanthrene, and pyrene carrying either an ethynyl (–C2H) or a butadiynyl (–C4H) group. Measurements were carried out in the mid-infrared at room temperature on grains embedded in CsI pellets and in the near-ultraviolet at cryogenic temperature on molecules isolated in Ne matrices. The infrared measurements show that interstellar populations of polyynyl-substituted PAHs would give rise to collective features in the same way as non-substituted PAHs give rise to the aromatic infrared bands. The main features characteristic of the substituted molecules correspond to the acetylenic CH stretching mode near 3.05 μm and to the almost isoenergetic acetylenic CCH in- and out-of-plane bending modes near 15.9 μm. Sub-populations defined by the length of the polyynyl side group cause collective features which correspond to the various acetylenic CC stretching modes. The ultraviolet spectra reveal that the addition of an ethynyl group to a non-substituted PAH molecule results in all of its electronic transitions being redshifted. Due to fast internal energy conversion, the bands at shorter wavelengths are significantly broadened. Those at longer wavelengths are only barely affected in this respect. As a consequence, their relative peak absorption increases. The substitution with the longer butadiynyl chain causes the same effects with a larger magnitude, resulting in the spectra showing a prominent if not dominating π-π* transition at long wavelengths. After discussing the relevance of polyynyl-substituted PAHs to astrophysics, we conclude that this class of highly conjugated, unsaturated molecules represents valid candidates for the carriers of the diffuse interstellar bands.

First enantioselective total synthesis of neocarazostatin B, determination of its absolute configuration and transformation into carquinostatin A

The first enantioselective total synthesis of neocarazostatin B, the determination of its absolute configuration and transformation into carquinostatin A are described.

Quantitative Structure–Retention Relationships for Polycyclic Aromatic Hydrocarbons and their Oligoalkynyl‐Substituted Derivatives

Abstract Reversed‐phase high‐performance liquid chromatography (RP‐HPLC) has been carried out for a series of unsubstituted polycyclic aromatic hydrocarbons (PAHs) and the corresponding ethynyl, 1,3‐butadiynyl, and 1,3,5‐hexatriynyl derivatives. Theoretical values of the isotropic polarizability and several polarity descriptors have been computed for each compound by using semiempirical models and density functional theory (DFT), with the aim of evaluating linear functions as quantitative structure–retention relationships (QSRRs). The polarity has been described by using either the permanent electric dipole moment, the subpolarity, or a topological electronic index. Three types of partial atomic charges have been used to calculate the subpolarity and a topological index. The choice of the theoretical model, of the polarity descriptor, and of the partial atomic charges is discussed and the resulting QSRRs are compared. Calculating the retention times from the polarizability and the topological electronic index (AM1, PM3, or DFT‐B3LYP/6–31+G(d,p)) gives the best agreement with the experimental values.

Phosphorylated glycosphingolipids essential for cholesterol mobilization in Caenorhabditis elegans

The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is indispensable. Here, we present a novel class of C. elegans phosphorylated glycosphingolipids, phosphoethanolamine glucosylceramides (PEGCs), capable of rescuing larval arrest induced by sterol starvation. We describe the total synthesis of a major PEGC species and demonstrate that the PEGC synthetic counterpart suppresses the dauer-constitutive phenotype of Niemann-Pick C1 (NPC1) and DAF-7/TGF-β mutant worms caused by impaired intracellular sterol trafficking. PEGC biosynthesis depends on functional NPC1 and TGF-β, indicating that these proteins control larval development at least partly through PEGC. Furthermore, glucosylceramide deficiency dramatically reduced PEGC amounts. However, the resulting developmental arrest could be rescued by oversaturation of food with cholesterol. Taken together, these data show that PEGC is essential for C. elegans development through its regulation of sterol mobilization.