Fr Francium

The HGF/c-Met signaling pathway mediates a variety of important biological activities, but dysregulation of the pathway is also closely associated with poor prognosis in a wide range of human cancers. c-Met is considered to be among the most promising therapeutic targets for anticancer drug discovery. Herein we report the discovery of a series of O-linked triazolotriazines that show sub-nanomolar inhibition of c-Met activity. Among these new compounds, 6 a exhibits high c-Met inhibitory potency in both enzymatic and cellular assays with great selectivity.

Highly selective c-Met inhibitor: c-Met is considered one of the most promising therapeutic targets for anticancer drug discovery. Herein we report a series of O-linked triazolotriazines that inhibit c-Met at sub-nanomolar concentrations. Compound 6 a exhibits high c-Met inhibitory potency in both enzymatic and cellular assays with great selectivity.

3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives were synthesized, and their structures were confirmed by single-crystal X-ray diffraction. This reaction yields the 1,4-dicarboxamide derivatives rather than the 1,2-dicarboxamide derivatives. Their in vitro antitumor activities were evaluated against SGC-7901, HO-8910, MCF-7, and A-549 cells. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. One compound (IC₅₀=0.57 μM) was further evaluated in vivo against an A-549 xenograft in BALB/cA nude mice; it effected 76.4 % inhibition of tumor weight through intraperitoneal (i.p.) administration of 40 mg kg⁻¹ body weight. Moreover, its acute toxicity was evaluated, and the i.p. LD₅₀ value was 325 mg kg⁻¹ in mice.

Tumor downsizing: A series of tetrazine derivatives were synthesized and characterized. Their antitumor activity in vitro showed several compounds to be endowed with cytotoxicity in the low micromolar range. The activity of one compound in vivo and its acute toxicity were further evaluated. The results revealed that it has relatively low toxicity and good efficacy.

RSC, Cambridge 2012. xii, 164 pp., hardcover £99.99.—ISBN 978-1-84973-017-4

The cover picture shows a molecular model of the natural product analogue halofuginone and the life cycle of the malaria parasite that requires a mosquito vector, the sequential infection of mammalian liver cells, followed by the invasion of red blood cells. Halofuginone is a synthetic derivative of the plant alkaloid febrifugine, which constitutes the active component of “Chang Shan”—a traditional Chinese medicine prepared from the roots of the blue evergreen hydrangea Dichroa febrifuga. Both compounds have been widely recognized for their activity in the symptomatic blood stage of malaria. We have discovered that halofuginone also potently inhibits the early- and late-liver-stage processes, clearing parasites one day after liver cell infection, a feature that is uncommon for most antimalarial agents. This finding reveals that halofuginone has potential as a prophylactic that could prevent the progression of the disease to the life-threatening blood stage. For more details, see the Full Paper by Emily R. Derbyshire, Ralph Mazitschek and Jon Clardy on p. 844 ff.

The inside cover picture shows that replacement of the ester bond in cyclic lipodepsipeptide antibiotics with an amide bond affords equipotent analogues with improved serum stability. The amide derivatives show improved selectivity for bacterial over host cells, probably due to their lower overall hydrophobicity and amphiphilicity. For more details, see the Full Paper by Predrag Cudic et al. on p. 871 ff.

Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B–D as the major metabolites, together with six minor metabolites, the new ningalins E–G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.

Chemical investigation of an Australian Didemnum species returned known ningalins B–D as the major metabolites, together with six minor metabolites, previously unknown ningalins E–G and known lamellarins Z, G and A6. These natural products were shown inhibit neurodegenerative disease kinase targets, casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β).

The Eph–ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph–ephrin antagonist that is able to inhibit EphA2 receptor activation; it is therefore potentially useful as a novel EphA2 receptor-targeting agent. Herein we explore the structure–activity relationships of a focused set of lithocholic acid derivatives based on molecular modeling investigations and displacement binding assays. Our exploration shows that while the 3-α-hydroxy group of lithocholic acid has a negligible role in recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrinA1 to EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits the EphA2–ephrinA1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand binding domain of EphA2, with a steady-state dissociation constant (K_D) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 as well as cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrinA1 ligand. These findings suggest that cholanic acid can be used as a template structure for the design of effective EphA2 antagonists, and may have potential impact in the elucidation of the role played by this receptor in pathological conditions.

Well worth theEphort! A combined application of computational and experimental techniques led to the identification of (5α)-cholan-24-oic acid derivatives that disrupt the ephrinA1–EphA2 complex by specific interaction with the ligand binding domain of the EphA2 receptor. SAR studies provide a detailed analysis of the requirements for small molecules able to disrupt the Eph–ephrin interaction. As this system plays a critical role in tumor and vascular functions during carcinogenesis, these compounds could provide leads for therapeutic agents.