α-Galactose based neoglycopeptides. Inhibition of verotoxin binding to globotriosylceramide

Solution and solid phase strategies for the synthesis of α-galactose based neoglycopeptide derivatives Figure 2, Figure 3, Figure 3, Scheme 3 and Scheme 4 were developed. Neoglycopeptides generated were tested for the inhibition of verotoxin binding to globotriosylceramide (Gb3) using ELISA. Among all of the compounds tested, only the lipid derivatives of neoglycopeptides, Figure 3 and Scheme 4 and Figure 3 and Scheme 4 were found to be inhibitors, IC₅₀=2.0 mM (Figure 3 and Scheme 4) and 0.2 mM (Figure 3 and Scheme 4). All of the inhibitors ( Figure 3 and Scheme 4) have a similar branching of the two α-galactosyl units at the N-terminal glycine residue of a short peptide and a lipid moiety attached at the C-terminal site. Both of these factors seem to be crucial for the inhibition. It is interesting to note that the inhibitors have only a portion of the natural trisaccharide ligand. The secondary groups either may contribute in sub-site oriented interactions with the protein receptors or may mimic the internal sugar units of the cell-surface ligand, Gb3.     

Novel dimeric Smac analogs as prospective anticancer agents

A small library of monovalent Smac mimics with general structure NMeAla-Tle-(4R)-4-Benzyl-Pro-Xaa-cysteamide, was synthesized (Xaa = hydrophobic residue). The library was screened in vitro against human breast cancer cell lines MCF-7 and MDA-MB-231, and two most active compounds oligomerized via S-alkylation giving bivalent and trivalent derivatives. The most active bivalent analogue SMAC17-2X was tested in vivo and in physiological conditions (mouse model) it exerted a potent anticancer effect resulting in ∼23.4 days of tumor growth delay at 7.5 mg/kg dose. Collectively, our findings suggest that bivalent Smac analogs obtained via S-alkylation protocol may be a suitable platform for the development of new anticancer therapeutics.     

BET bromodomain proteins are required for glioblastoma cell proliferation

Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.     

Heteroannelated and 7-deoxygenated goniofufurone mimics with antitumour activity: Design,synthesis and preliminary SAR studies

Cytotoxic (+)-goniofufurone mimic such as benzoxepane 2 was preferentially formed after the treatment of 7-O-benzoyl-5-O-benzyl (+)-goniofufurone derivative 6 with titanium(IV) fluoride. However, the corresponding 7-epimer 5 (derivative of 7-epi-goniofufurone) under the similar reaction conditions gave mainly 7-deoxy derivative 7 as a result of an unexpected 1,5-hydride shift. Extension of this methodology to the enantiomer ent-6 provided cytotoxic (?)-goniofufurone mimics ent-2 and ent-7. Synthesized compounds showed diverse growth inhibitory effects against selected tumour cell lines, but were devoid of any significant toxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that are beneficial for their antiproliferative activity, such as presence of an additional oxepane ring, the absolute stereochemistry and the presence of a deoxy function at the C-7 position.     

Potent inhibition of norovirus by dipeptidyl α-hydroxyphosphonate transition state mimics

The design, synthesis, and evaluation of a series of dipeptidyl α-hydroxyphosphonates is reported. The synthesized compounds displayed high anti-norovirus activity in a cell-based replicon system, as well as high enzyme selectivity.     

Synthesis and antimicrobial activity of small cationic amphipathic aminobenzamide marine natural product mimics and evaluation of relevance against clinical isolates including ESBL–CARBA producing multi-resistant bacteria

A library of small aminobenzamide derivatives was synthesised to explore a cationic amphipathic motif found in marine natural antimicrobials. The most potent compound E23 displayed minimal inhibitory concentrations (MICs) of 0.5–2 μg/ml against several Gram-positive bacterial strains, including methicillin resistant Staphylococcus epidermidis (MRSE). E23 was also potent against 275 clinical isolates including Staphylococcus aureus, Enterococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, as well as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and ESBL–CARBA producing multi-resistant Gram-negative bacteria. The study demonstrates how structural motifs found in marine natural antimicrobials can be a valuable source for making novel antimicrobial lead-compounds.     

Morphological effects of juvenile hormone mimics on embryonic development in the bug,Pyrrhocoris apterus

Summary Embryos ofPyrrhocoris apterus exposed to juvenile hormone mimics (JH) were examined throughout development to determine the progressive effects of treatment. Prior to blastokinesis whole experimental embryos did not differ morphologically from control embryos fixed at the same stage. Treated embryos failed to complete blastokinesis due to abnormal breakage of the extra-embryonic membranes.In the embryo-larva transition, JH exposure interfered with dorsal closure, with the consolidation of the nerve cord, and with the extension of appendages. Yet pigmentation and muscle differentiation occurred.These effects were interpreted and discussed with reference to the role of juvenile hormone in post-embryonic development.This is a portion of a dissertation submitted to the graduate school of Harvard University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy (1973). It was previously reported in abstract (Enslee and Riddiford, 1970). This research was supported by NIGMS Training Grant T01 GM 00036-09, 11, 12, 13 to E.C.E. and NSF grants GB 6730, GB 7966 to L.M.R.     

Alpha-galactose based neoglycopeptides. Inhibition of verotoxin binding to globotriosylceramide

Solution and solid phase strategies for the synthesis of alpha-galactose based neoglycopeptide derivatives 2-13 were developed. Neoglycopeptides generated were tested for the inhibition of verotoxin binding to globotriosylceramide (Gb3) using ELISA. Among all of the compounds tested, only the lipid derivatives of neoglycopeptides, 11, 12 and 13 were found to be inhibitors, IC50 = 2.0 mM (11b and 12c) and 0.2 mM (11c and 13c). All of the inhibitors (11b, 11c, 12c and 13c) have a similar branching of the two alpha-galactosyl units at the N-terminal glycine residue of a short peptide and a lipid moiety attached at the C-terminal site. Both of these factors seem to be crucial for the inhibition. It is interesting to note that the inhibitors have only a portion of the natural trisaccharide ligand. The secondary groups either may contribute in sub-site oriented interactions with the protein receptors or may mimic the internal sugar units of the cell-surface ligand, Gb3.     

A novel approach to the stereocontrolled synthesis of C-vinyl beta-D-galactopyranosides

Reaction of a lithiated dithiinyl reagent with a O-perbenzylated D-glycono-delta-lactone readily generates the corresponding masked C-vinyl galactosides in high yields and full beta-selectivity. Removal of the sulfur mask renders the free vinyl aglycone with the vinyl group in either the Z or E configuration, depending on the desulfurization conditions chosen.