The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC = 19.1 μM) and Fasciola hepatica (IC = 17.7 μM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fascioliasis, respectively. Here, we aimed to increase the potency of 7-keto-sempervirol by total synthesis of 30 structural analogues. Subsequent screening of these new diterpenoids against juvenile and adult lifecycle stages of both parasites as well as the human HepG2 liver cell line and the bovine MDBK kidney cell line revealed structure-activity relationship trends. The most active analogue, 7d, displayed improved dual anthelmintic activity over 7-keto-sempervirol (IC ≈ 6 μM for larval blood flukes; IC ≈ 3 μM for juvenile liver flukes) and moderate selectivity (SI ≈ 4-5 for blood flukes, 8-13 for liver flukes compared to HepG2 and MDBK cells, respectively). Phenotypic studies using scanning electron microscopy revealed substantial tegumental alterations in both helminth species, supporting the hypothesis that the parasite surface is one of the main targets of this family of molecules. Further modifications of 7d could lead to greater potency and selectivity metrics resulting in a new class of broad-spectrum anthelmintic.

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.

The development of anti-metastatic drugs is an urgent healthcare priority for cancer patients, since metastasis is thought to account for around 90% of cancer deaths. Current antimetastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-B family, is associated with poor prognosis in a range of tumor types. Bcl3 has been directly implicated in the metastasis of tumor cells, yet is well tolerated when constitutively deleted in murine models, making it a promising therapeutic target. Here we describe the identification and characterization of the first small molecule Bcl3 inhibitor, by employing a virtual drug design and screening approach against a computational model of the Bcl3-NFkB1(p50) protein-protein interaction. From selected virtual screening hits, one compound (JS6) showed potent intracellular Bcl3-inhibitory activity. JS6 treatment led to reductions in Bcl3-NFkB1 binding, tumor colony formation and cancer cell migration in vitro; and tumor-stasis and anti-metastatic activity in vivo, whilst being devoid of overt systemic toxicity. These results represent a successful application of in silico screening in the identification of protein-protein inhibitors for novel intra-cellular targets, and confirm Bcl3 as a potential anti-metastatic target.

NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Analysis of existing inhibitor scaffolds and early structure−activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogues in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.

A microwave enhanced synthesis of prodrug nucleotide (ProTide) analogues is presented.

Several Cord Blood (CB) Bank studies suggested that ethnicity impaired CB unit (CBU) qualification. The Bone Marrow Donors Worldwide registries present an over-representation of unrelated donors (UD) from Northwestern European descent. This raises the question of equality of access to hematopoietic stem cells transplant, especially in the Mediterranean zone, which has taken in many waves of immigration. The aim of our study is to address whether, in the Marseille CB Bank, CBU qualification rate is impaired by geographic origin. The study compared biological characteristics of 106 CBU disqualified for total nucleated cell (TNC) count (dCBU) and 136 qualified CBU in relation to registry enrichment and haplotype origin. A high proportion (480%) of both dCBU and CBU had at least one non-European haplotype and enrich CB and UD registries to a higher extent than those with two European haplotypes (P o 0.001). No difference was observed between TNC count and volume according to geographic origin. Our study shows that diverse Mediterranean origins do not have an impact on the CBU qualification rate. Partnership with Mediterranean birth clinics with highly trained staff is a reasonable option to increase the HLA diversity of CB Bank inventories and to improve the representation of minorities.

Interaction with cardiac ion channels can potentially result in severe or even fatal cardiac side effects. The most prominent of cardiac channels, human ether-a-go-go-related gene (hERG), voltage-gated sodium channel 1.5 (NaV1.5) and voltage-gated calcium channel 1.2 (CaV1.2), which traffic major ion currents shaping cardiac action potential, are recognized as primary counter-screen targets. These channels possess relatively large inner pores with multiple binding sites and can accommodate a variety of structurally diverse ligands. This chapter provides a short overview of in vitro approaches in preclinical cardiotoxicity screening, gives a summary of available structural data and pharmacophore models for hERG, NaV1.5 and CaV1.2 as well as discusses medicinal chemistry strategies that were successfully applied to mitigate cardiotoxicity risk. The major highlighted approaches are lipophilicity reduction, basicity reduction and removal or modification of (hetero)aromatic substituents. The strategies are illustrated by multiple examples from recent literature.

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