ChemMedChem

The cover picture shows the hypothetical binding motif of a novel potent protein kinase CK2 inhibitor, 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one, which shows a K_i value of 7 nM. CK2 is a ubiquitous, essential, and highly pleiotropic protein kinase, and abnormally high constitutive activity of this enzyme is thought to mediate its pathogenic potential in neoplasia and other diseases, such as viral infections and inflammatory diseases, like glomerulonephritis. Starting from the previous identification of highly active 3,8-dibromo-7-hydroxy-4-methylchromen-2-one and ellagic acid (K_i=20 nM and 60 nM, respectively), an X-ray-driven “cut & paste approach” was applied to design a novel series of urolithins as potent CK2 inhibitors. For more details, see the Full Paper by Stefano Moro et al. on p. 2273 ff.

The inside cover picture shows a nontoxic targeting system programmed for the selective delivery of three different cytotoxic agents to the tumor site. This system includes a chemical amplifier that transforms a single tumor-associated enzymatic triggering event into the release of a highly toxic drug cocktail. For more details, see the Communication by Sébastien Papot et al. on p. 2137 ff.

“The biggest challenge facing the drug discovery community is … to come up with sustainable business models that will ensure a future for innovative pharmaceutical research and deliver drugs.” This and more from Prof. Jürgen Bajorath can be found on page 2131.

As a matter of FACT! Carbazoles known as curaxins effectively bind the heterodimeric protein complex, FACT, the sequestration of which causes promotion of multiple pathways (p53 activation and NF-κB inhibition) leading to tumor cell death, without inducing DNA damage. Given these results, curaxins hold promise for the development of effective anticancer therapies with decreased toxicity.

Amplified action! We developed the therapeutic first targeting system that includes a chemical amplifier programmed both to release two potent anticancer drugs after a single enzymatic activation step and become cytotoxic itself once the amplification process is completed.

Grubbs up! Grubbs-type catalysts have potential as inhibitors of tumor-relevant enzymes, exhibit antiproliferative effects in cultured tumor cells, and influence cell metabolism. While the potencies of these catalysts are poor to moderate from a drug development prospective, their biological activity suggests that incorporating aspects of their structures could be beneficial for drug design.

A combination of three methods—molecular docking (virtual screening), saturation transfer difference (STD)-NMR screening, and a fluorescence-based activity assay—were used to screen a fragment library for potential lead fragments displaying inhibition of the phosphatase activity of soluble epoxide hydrolase, an enzyme involved in pathophysiologically relevant processes, including proliferation and apoptosis.

Progression of compound activity in target space: We introduce the concept of activity profile sequences to organize compound series into sets of structures active against stepwise increasing numbers of targets. Shown is an exemplary sequence containing a conserved scaffold representing compounds with activity against up to four targets (A–D).

An old dog with new tricks! While sulindac, a nonsteroidal anti-inflammatory drug (NSAID), has been extensively investigated as an anticancer agent, its mechanism of action remains poorly understood. The crystal structure of aldose reductase (ALR) in complex with sulindac rationalizes its inhibition of this enzyme—formerly considered an antidiabetic target—as a key mechanism for antitumor activity and supports further evaluation of ALR inhibitors as anticancer and antiproliferative drugs.

Virtual reality: Although crystallographic structure data and related information have been reported for class A GPCRs, herein we report the first use of structure-based virtual screening to identify new allosteric modulators of class B GPCRs. Despite the modest activities of the identified compounds, this study provides a novel in silico approach for the discovery of future class B GPCR modulators.

Target specificity: Successful 3D pharmacophore-based virtual screening resulted in the first small, drug-like molecule that stimulates the activity of kallikrein-related peptidase 3 (KLK3, PSA). The compound discovered can be applied to the design of novel KLK3-stimulating compounds with the potential to inhibit tumor angiogenesis and progression of prostate cancer.

C3′ is prime: In our continued efforts to optimize the isoCA-4 skeleton, we synthesized and evaluated a new series of 1,1-diaryl compounds in which the 3′-hydroxy group of isoCA-4 is replaced by various substituents. Compounds 8 and 17, respectively bearing allylic and propargylic alcohol functions at C3′, were found to have the most potent antiproliferative activity against a panel of cancer cell lines at the nanomolar level.

R₈-conjugated PNAs for uptake! A polyarginine–PNA conjugate that targets microRNA-210 (Rpep-PNA-a210, or miR-210) shows high affinity for RNA, efficient uptake into target cells without the need for transfection reagents, and potent inhibitory effects toward the biological activity of microRNA-210.

Mutations that cause resistance to NNRTIs and treatment failure in patients were analyzed by means of computational and statistical methods. Data for first- and second-generation NNRTIs related to the single RT mutation K103N were in agreement with the unfavorable energetic profile observed with respect to the wild-type sequence. Interestingly, according to the phenotypic profile, the increased affinity for K103N/S mutants displayed by the potent agent diarylpirimidine etravirine was characterized by high conformational flexibility.

Selective at last: [1,2,4]Triazolo[1,5-a]pyridines, aminopyrazoles, and disubstituted ureas were explored as potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3–cyclin 6 complex. Optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin-dependent kinase CDK2.

Antiviral agents: A series of new diarylpyrimidine (DAPY) derivatives with a ketone hydrazine substituent on the CH₂ linker between the pyrimidine nucleus and the phenyl ring were synthesized, and their anti-HIV activity in MT-4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild-type HIV-1, with EC₅₀ values in the range of 1.7–13.2 nM.

Weighing the pros and cons: The systematic development and characterisation of novel prodrugs of the antiprotozoal drug pentamidine is described. The prodrug principles applied use different enzyme systems for activation and target both passive and active uptake mechanisms. Through the synthesis and in vitro and in vivo evaluation of eight novel prodrugs, reliable conclusions regarding the most appropriate prodrug principle for this drug were drawn.

Fight against the film: 4,5-Disubstituted-2-aminoimidazole–triazole conjugates (2-AITs) were developed and investigated for antibiofilm activity and antibiotic resensitization. This class of small molecules was found to inhibit biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii at micromolar concentrations. Conventional antibiotic resensitization was also observed for lead compounds.

Two new families: In this work we identified two new classes of potent antitubercular agents. Synthesis and analysis of the pharmacological properties of several analogues led to the discovery of potent and selective derivatives in vitro, with moderate in vivo activity.

Molecular copycats! Isoxazoline-containing peptidomimetics, designed to be effective α_vβ₃ and α₅β₁ integrin ligands, were synthesized by hydroxyamine conjugate addition to alkylidene acetoacetates followed by intramolecular hemiketalization. Cell adhesion assay results suggest a very effective ligand–receptor interaction, as confirmed by docking studies.

Two become one: Comparing the crystallographic binding modes of ellagic acid (red) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC; blue), an X-ray structure-driven merging approach to the design of novel casein kinase 2 (CK2) inhibitors was taken. Using this strategy, a potent and selective urolithin derivative, 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one was identified, which exhibits a K_i value of 7 nM against CK2.

Fighting firewithfire: Malignant pleural mesothelioma cells are chemoresistant thanks to glutathione (GSH), which deactivates Pt-based drugs. Ethacrynic acid (EA) inhibits the enzyme that catalyzes the conjugation between GSH and Pt drugs. We therefore synthesized and characterized a bifunctional drug—a Pt^II complex containing EA—and tested it on four mesothelioma cell lines in comparison with its analogue Pt^IV complex, ethacraplatin.

Paddling the Rhein: Two series of rhein analogues were synthesized with modification at the 3-position. Their cytotoxicities were evaluated using an MTT assay, and among all analogues, 8 showed the best potency, with an IC₅₀ value of 0.6 μM against the MOLT4 cell line.

Fragmentized! After developing and applying a graph-based approach to “frequent substructure” mining, we performed a virtual screen on the adenosine A_2A receptor and retrieved active compounds from vendor databases. The compound shown here displayed a K_i value on the A_2A receptor of 770 nM.

Stop the clot: Small molecular antifibrinolytic agents in clinical use such as tranexamic acid carry the risk of prompting thrombus formation. Herein we present an investigation of pyrolo[1,2:4,5]-1,4-dioxopyrazino[1,2:1,6]pyrido[3,4-b]indoles (DAPPP), some of which show strong hemostatic activities in vivo. The most potent compound, 5 c, has a good therapeutic window for antifibrinolytic therapy.

CRC Press, Boca Raton 2010. 630 pp., hardcover $ 99.95.—ISBN 978-1-4200-8772-7

Wiley-VCH, Weinheim 2011, 396 pp., hardcover $ 190.00.—ISBN 978-3-527-31790-5