Unexpected inhibition : 2‐ and 4‐mono‐ and difluoromethyl estrone sulfate derivatives are suicide inhibitors of steroid sulfatase (STS). Kinetic studies suggest that inhibition by the monofluoro derivatives is a result of a quinone methide intermediate that reacts with active‐site nucleophiles, whereas the main inhibition pathway of the 4‐difluoromethyl derivative is a result of decomposition of the initial quinone methide to an aldehyde that acts as potent, almost irreversible inhibitor.
Bridging the gap : The differences between medicinal chemistry at the industrial and academic levels raises the question: Is there a significant gap between the two spheres that requires attention, or should such differences be deemed natural, without the need to close the gap? Herein we provide perspectives on this issue, based in part on opinions expressed at a forum discussion held at ISMC 2008 in Vienna.
Protein compatible . Olefin metathesis has emerged as a viable strategy for site‐selective protein modification. This minireview traces its development from early peptide models and metathesis in water to its ultimate application to protein substrates. Prospects in chemistry and biology are also discussed.
Less stress : We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. Novel benzamide‐based ligands selectively inhibit HDAC3 but provide no neuroprotection in the HCA–cortical neuron model of oxidative stress.
PDE7 inhibitors regulate pro‐inflammatory and immune T‐cell functions, and are a potentially novel class of drugs particularly useful for treatment of a wide variety of immune and inflammatory disorders. Structural optimization of thioxoquinazoline derivatives led to new compounds with very interesting profiles as PDE7 or PDE7/PDE4 dual inhibitors, which may be further developed as new drugs for inflammatory and neurological diseases.
Light up galectin: Photoprobes based on thiodigalactoside were prepared for galectin‐3, a lectin linked to cancer. The probes contained either benzophenone or acetophenone moieties as the photolabel for covalent attachment to the protein. One particular probe labeled galectin‐3 selectively, even in the presence of cell lysate.
Finding the right fit : Herein, we report on the development of novel steric probes and present initial insights into their interplay with DNA polymerases. Our findings provide experimental evidence for varied enzyme–substrate interactions that might account for the varied selectivity previously observed.
Access to enantiopure β‐amino acids : β‐Aminopeptidases are hydrolases that possess the unique ability to cleave N‐terminal β‐amino acids from peptides and amides. Hydrolysis of racemic β‐amino acid amides catalyzed by these enzymes displays enantioselectivity with strong preference for substrates with the L ‐configuration, and gives access to various aliphatic β‐amino acids of high enantiopurity.
Natural product libraries for SAR studies : We used a chemical array platform to study the SARs of bleomycin (BLM) derivatives and Shble protein. The on‐chip SARs suggested that several domains are important for recognition of BLMs by Shble protein. In particular, the C‐terminal tail and the propionamide moiety in pyrimidoblamic acid (PBA) were shown to be important for the binding.
Molecules that inhibit store‐operated calcium entry (SOCE) are potentially useful immunomodulating agents. The identification of proteins involved in this pathway may further enable the identification of selective inhibitors. Herein we document some examples of the small‐molecule inhibitors of SOCE that have been reported to date. We also describe methods that were used to characterize the mechanism of action of these inhibitors.
An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago‐potentiator ADX‐47273. This effort identified key substituents in the 3‐position of oxadiazole that engendered either mGluR5 ago‐potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9‐fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.
Direct stimulation of soluble guanylate cyclase (sGC) represents a promising therapeutic strategy for the treatment of a range of diseases, including the severely disabling pulmonary hypertension (PH). Optimization of the unfavorable DMPK profile of previous sGC stimulators provided riociguat, which is currently being investigated in phase III clinical trials for the oral treatment of PH.
Reducing virulence : RhlI catalyzes the synthesis of N‐butanoyl homoserine lactone (BHL), with a minor product N‐hexanoyl homoserine lactone (HHL). By using directed evolution and a genetic screen, RhlI has been engineered for enhanced production of both BHL and HHL at a similar level.
Oxidation of a specific cysteine residue to Cα‐formylglycine is a novel post‐translational modification that is directed by a short recognition motif commonly found in pro‐ and eukaryotic sulfatases. As recently shown by C. Bertozzi and co‐workers, this system can be employed in protein engineering to equip proteins with genetically encoded aldehyde tags for site‐specific labeling, conjugation and immobilization.
By miscounting the number of malonyl‐CoA condensations, the stilbene synthase (STS) from Pinus sylvestris forms the previously unknown pentaketide, 2‐malonylresveratrol, in addition to the expected tetraketide resveratrol (see scheme). This is the first time that such tetra‐ and pentaketide‐CoA derivatives have been observed; this suggests that these products might be free intermediates in the biosynthesis of stilbenes.
Tailor made : We report the rational biosynthesis of C15 hydroxylated non‐quinone geldanamycin analogues by site‐directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post‐PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound.
Combinatorial biosynthesis meets combinatorial pharmacology, cyanobacterial style : A new antimitotic natural product with features of both dolastatins 10 and 15 was isolated from the same Floridian Symploca sp. sample that produced the histone deacetylase inhibitor largazole. Both agents in combination are more effective in inhibiting cancer cell proliferation than either agent alone.
Setting the right target : Most researchers who use small RNAs in mammalian cells assume that mRNA will be the target. Recent studies suggest that small RNAs can also target chromosomal DNA.
Special delivery! An aptamer‐directed anticancer drug was molecularly engineered to be delivered to target cells for efficient therapeutic application. The covalent conjugation of drug and aptamer creates alternative opportunities for targeted therapy, as multiple yet specific aptamers can be “generated” relatively easily by cell‐SELEX for any target cells; this demonstrates the full potential of cell‐SELEX as a molecular discovery tool for biomedical studies and drug development.
A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild‐type HIV‐1.
