ChemMedChem

The cover picture shows the concept of disulfide-constrained miniproteins as alternatives to antibodies for the development of new chemical entities. Their structural characteristics and beneficial pharmacokinetic profile highlight this peptide format for the engineering of novel diagnostic imaging agents. Here, the chemical synthesis of the scaffold Min-23 and its functionalization for in vitro and in vivo applications are described. For more details, see the Full Paper by Walter Mier et al. on p. 237 ff.

The inside cover picture shows how RAFT polymerisation technology can be used to construct well- defined drug–polymer conjugates by growing a polymer of desired length, composition and architecture from a specific point of the drug molecule. RAFT is a powerful alternative to PEGylation that provides medicinal chemists with a “second chance” to adjust the solubility and bioavailability of bioactive molecules. For more details, see the Full Paper by J. Tsanaktsidis, B. Lepenies et al. on p. 281 ff.

The back cover picture shows a novel CXCR4-targeted antagonist blocking the SDF-1/CXCR4 interaction, resulting in mobilization of various stem cells, particularly the CD34⁺ cell type, from the bone marrow to the peripheral blood circulating system. Hematopoietic stem cells thus collected can be potentially applied to autologous transplantation to help cancer patients restore their immune system rapidly after undergoing chemo- or radiotherapy. For more details, see the Communication by Kak-Shan Shia et al. on p. 209 ff.

“When I was eighteen, I wanted to be … a doctor: “Where there is love of mankind, there is also love of the art of medicine” (Hippocrates).” This and more from Prof. Mouâd Alami can be found on page 193.

Where are we now? Today genomics technologies are firmly embedded in the drug discovery process. Here, we describe how approaches, such as structural genomics and family-wide screening, which derived from the human genome sequencing project are being applied by medicinal chemists to discover potent and selective new drugs.

Supramolecular interference: A synthetic peptide mimetic of the trimeric form of gp41 showed significantly increased inhibitory activity against the HIV-1 fusion mechanism. This study demonstrates a useful strategy for the design of effective inhibitors against viral infections that proceed by membrane fusion with host cells.

Going mobile: Based on screening hit 1, a novel class of polyamine compounds, as represented by compound 8, were identified as potent and selective CXCR4 antagonists. CXCR4-targeted molecules, as demonstrated by the marketed AMD3100 and 8, are able to mobilize stem cells from bone marrow effectively and are expected to have broad utility in cell therapy and regenerative medicine.

The sincerest form of flattery! A novel, symmetric lipid A mimetic (D1) formed by two glucose units linked through a 6-6' succinic diamide linker is active in modulating the activity of human TLR4. D1 inhibits endotoxin-stimulated TLR4 activation by inhibiting interaction of endotoxin with both receptors CD14 and MD-2 (associated to TLR4). D1 also has weak TLR4 agonist activity that makes it a promising lead compound for development as a vaccine adjuvant.

More than herbal remedies: Subglutinols A and B, natural diterpenoid pyrone immunosuppressive agents, and their synthetic intermediates were assayed to assess their functional mechanisms of immune modulation. Subglutinol A and its methyl-γ-pyrone derivative (10) significantly suppressed interleukin-2 production (IC₅₀) by different T cells, and also efficiently inhibited the T cell expression of activation markers, CD25 and CD69. These preliminary results suggest the subglutinol structure as a lead for the design of novel immunosuppressive agents.

Shoot the messenger! CD38 is a multifunctional enzyme responsible for the generation of calcium ion messengers. A structural optimization was carried out to develop noncovalent CD38 inhibitors based on hit compound S125 (top) (IC₅₀=86 μM). The best compound inhibited CD38 NADase with an IC₅₀ value of 4.7 μM (bottom). Molecular modeling was used to predict potentially important interactions between the inhibitor and enzyme.

Stable conjugates: Two pivaloxymethyl (POM) groups were introduced at the 3- and 7-hydroxy groups of quercetin to provide a 3,7-bis-O-POM derivative (shown) with exceptional stability in cell culture media and efficient cellular uptake. Hydrolyzed to the 3-O-POM derivative in cytoplasm, the quercetin conjugate exhibits a significant cytostatic effect in various cancer cell lines.

BBC news: CC bond formation reactions are underused by medicinal chemists for the preparation of libraries of compounds with good drug-like (“rule-of-five”) and drug fragment-like (“rule-of-three”) properties. Herein we demonstrate the versatility of the Barluenga boronic coupling (BBC) for the preparation of small drug-like and drug fragment-like compounds in parallel.

Small but smart: Miniproteins are scaffolds for the development of alternative non-immunoglobin binding entities. Their structural characteristics and excellent stability support the use of this peptide format for the engineering of novel diagnostic agents. Herein we present the total chemical synthesis of the disulfide-constrained scaffold Min-23 and its functionalization for in vitro and in vivo application.

Small highly soluble molecules were soaked into various protein crystals to detect binding hot spots with respect to hydrophobic and hydrophilic properties. These hot spots were subjected to computational active site mapping with an approach using knowledge-based pair potentials to detect favorable binding positions for various atom types. Our findings confirm the central hypothesis of fragment-based lead discovery: binding poses, even of small probes, do not strongly deviate once a ligand is grown further into a binding site.

Analysis of hydrogen bonds involving fluorine found in small molecules listed in the Cambridge Structural Database (CSD) and in fluorinated natural products listed in the Protein Data Bank (PDB) identified a correlation between ¹⁹F NMR isotropic chemical shift and close F⋅⋅⋅HX contacts (with X=N or O), highlighting the role of shielded fluorine atoms in protein recognition, selectivity and chemical properties. Based on these findings, novel chemical scaffolds for recognizing distinct structural motifs in proteins are proposed.

Restricted twist: The excellent selectivity and oral efficacy of PH-797804 (green, at top) in preclinical disease models make it a suitable candidate for interrogating the role of p38 kinase as a therapeutic target, in contrast to its inactive atropisomer (in blue). PH-797804 is currently under phase II clinical investigation for the treatment of several inflammation-mediated diseases.

A life RAFT! A series of well-defined polymer–drug conjugates have been prepared to increase the bioavailability of the known cytotoxic drug 7-ethyl-10-hydroxycamptothecin (SN-38). Reversible addition–fragmentation chain transfer (RAFT) polymerisation was used to covalently and site-specifically append an N-(2-hydroxypropyl)methacrylamide (HPMA) polymer to SN-38. The poly-HPMA–SN-38 conjugates displayed excellent aqueous solubility, cytotoxic activity, and specificity for cancer cells.

Benefits of benzothiazoles: A series of substituted benzothiazoles were designed, synthesized, and evaluated for their anticancer activity and their capacity to block tubulin polymerization. Three have promising anticancer activity, while one compound effects cell-cycle arrest and inhibition of tubulin polymerization on par with combretastatin A-4. Modeling studies with the colchicine binding site gave insight into the SARs of these and other benzothiazole derivatives.

Tin can do it! A variety of tin(IV) carboxylate complexes were synthesized and characterized. Studies with a daunomycin-resistant K562/R cell line expressing P-glycoprotein (Pgp) showed that these complexes are not substrates of this protein pump, indicating that these compounds do not induce multidrug resistance associated with the overexpression of Pgp.

An Achilles' heel for tumors: The strict dependence of cancer cells on the glycolytic pathway for ATP generation led to the evaluation of lactate dehydrogenase (LDH) inhibitors as potential anticancer agents. We identified a compound, galloflavin, which combines inhibitory efficacy toward LDH-A and -B (in both purified enzyme and whole-cell assays) with a lack of toxicity toward cell respiration.

Unnatural influences: The SAR of apelin-13 with the APJ receptor was evaluated by D-Ala scan, replacement of Phe 13 and Pro 12, and the central portion with selected unnatural amino acids. The activity of the resulting analogues was tested in binding and functional assays on the G_i and β-arrestin2 pathways, and their stability in plasma assessed.

Leeching potent compounds: Tridegin is a potent factor XIIIa inhibitor, and is the only characterized peptidic compound that inhibits this target. Herein we describe the full synthesis of the 66-mer peptide and its analogues and show that some derivatives are cleaved as substrates. The region that interacts with the active site of the enzyme is located around a glutamine residue (Q⁵²) in the C-terminal part of tridegin.

Wiley-VCH, Weinheim 2011. 406 pp., hardcover € 138.00.—ISBN 978-3-527-32696-9