Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation.

The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far.

Plasma amyloid-β biomarkers are associated with Alzheimer's disease comorbidity in Lewy body disease.

No blood biomarkers which can identify Alzheimer's disease pathology in Lewy body disease (LBD) have ever been established. We showed that the plasma amyloid-β (Aβ) /Aβ ratio was significantly decreased in patients with Aβ+ LBD compared with those with Aβ- LBD and it might be a useful biomarker.

Deterioration after Liver Transplantation and Transthyretin Stabilizer Administration in a Patient with ATTRv Amyloidosis with a Leu58Arg (p.Leu78Arg) TTR Variant.

We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT.

Trimeric purine nucleoside phosphorylase: exploring postulated one-third-of-the-sites binding in the transition state.

Transition-state analogue inhibitors, immucillins, were reported to bind to trimeric purine nucleoside phosphorylase (PNP) with the stoichiometry of one molecule per enzyme trimer [Miles, R. W.; Tyler, P.

9-Deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid are slow-binding picomolar inhibitors of trimeric purine nucleoside phosphorylase.

Genetic deficiency of purine nucleoside phosphorylase (PNP; EC 2.4.2.

Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mammalian PNPs.

9-(5',5'-Difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) was designed as a multi-substrate analogue inhibitor against purine nucleoside phosphorylase (PNP) on the basis of X-ray crystallographic data obtained for a binary complex of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine (DFPP-G) with calf-spleen PNP. DFPP-DG and its analogous compounds were synthesized by the Sonogashira coupling reaction between a 9-deaza-9-iodoguanine derivative and omega-alkynyldifluoromethylene phosphonates as a key reaction. The experimental details focused on the synthetic chemistry along with some insights into the physical and biological properties of newly synthesized DFPP-DG derivatives are disclosed.

Antiproliferative activity of purine nucleoside phosphorylase multisubstrate analogue inhibitors containing difluoromethylene phosphonic acid against leukaemia and lymphoma cells.

Potent inhibitors of purine nucleoside phosphorylase (PNP) are expected to act as selective agents against T-cell tumours. Five compounds with guanine, three with hypoxanthine, and five with 9-deazaguanine, all connected by a linker with difluoromethylene phosphonic acid, were studied on their inhibitory potential against human and calf PNPs. Antiproliferative activity of these analogues against lymphocytes as well as lymphoma and leukaemia cells has been also investigated.

Overexpressed proteins may act as mops removing their ligands from the host cells: a case study of calf PNP.

Calf purine nucleoside phosphorylase (PNP) was overexpressed in Escherichia coli. The basic kinetic parameters of recombinant PNP were found to be similar to the values published previously for non-recombinant PNP from calf spleen. However, upon titration of the recombinant enzyme with the tight-binding multisubstrate analogue inhibitor DFPP-DG, endothermic as well as exothermic signals were obtained.

1.45 A resolution crystal structure of recombinant PNP in complex with a pM multisubstrate analogue inhibitor bearing one feature of the postulated transition state.

Low molecular mass purine nucleoside phosphorylases (PNPs, E.C. 2.

Diastereoselective synthesis of gamma-amino-delta-hydroxy-alpha,alpha-difluorophosphonates: a vehicle for structure-activity relationship studies on SMA-7, a potent sphingomyelinase inhibitor.

A highly diastereoselective synthesis of 2-amino alcohol derivatives bearing a difluoromethylphosphonothioate group at the 3-position was achieved through LiAlH(O-t-Bu)(3)-mediated reduction of the corresponding alpha-amino ketones. The phosphonothioate moiety of the product was readily converted into the corresponding phosphonate by oxidation with m-CPBA, followed by aqueous workup. The developed methods should be useful for SAR studies of SMA-7, a potent inhibitor of SMases.

Thermodynamic studies of interactions of calf spleen PNP with acyclic phosphonate inhibitors.

The Gibbs binding energy and entropy/enthalpy contributions to the interaction of calf spleen purine nucleoside phosphorylase (PNP) with the novel multisubstrate analogue DFPP-DG, as well as with DFPP-G and (S)-PMP-DAP were determined by fluorescence and calorimetric studies. Results were compared with findings for guanine - a natural reaction product and inhibitor.

9-Deazaguanine derivatives: synthesis and inhibitory properties as multi-substrate analogue inhibitors of mammalian PNPs.

9-(5',5'-Difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) and its related analogues were designed as multi-substrate analogue inhibitors of purine nucleoside phosphorylase (PNP) on the basis of the X-ray crystallographic data obtained for the binary complex of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine (DFPP-G) with calf spleen PNP. One of these analogues, homo-DFPP-DG was found to be a very potent PNP inhibitor at an intracellular (approximately 1 mM) phosphate concentration.

Inhibitory properties of nucleotides with difluoromethylenephosphonic acid as a phosphate mimic versus calf spleen purine nucleoside phosphorylase and effect of these analogues on the viability of human blood lymphocytes.

Several cyclic and acyclic 6-keto purine nucleotides with difluoromethylenephosphonic acid as phosphate mimic are proved to be potent inhibitors of mammalian purine nucleoside phosphorylase (PNP). Antiproliferative activity of these analogues on the growth of human blood lymphocytes was tested by MTT assay. Compared to inhibitory effects on the growth of human blood T-lymphocytes isolated from healthy donors, all analogues significantly slow down proliferation of T-lymphocytes isolated from patients with autoimmune thyroid disease--Hashimoto's thyroiditis.

Synthesis and evaluation of 9-deazaguanine derivatives as multi-substrate analogue inhibitors of PNP.

9-(5',5'-Difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) and its related analogues were designed as multi-substrate analogue inhibitors against purine nucleoside phosphorylase (PNP) on the basis of the X-ray crystallographic data obtained for the binary complex of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine (DFPP-G) with calf-spleen PNP. One of these analogues, homo-DFPP-DG was found to be a very potent PNP inhibitor at an intracellular P(i) concentration (about 1 mM phosphate).

Synthesis and biological evaluation of 9-deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid as multi-substrate analogue inhibitors of PNP.

9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) was designed as a multi-substrate analogue inhibitor against purine nucleoside phosphorylase (PNP) on the basis of X-ray crystallographic data obtained for a binary complex of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine (DFPP-G) with calf spleen PNP. DFPP-DG and its analogous compounds were adjusted by length of the linker achieved by the Sonogashira-coupling reaction between a 9-deaza-9-iodoguanine derivative and omega-alkynyldifluoromethylene phosphonates as a key reaction. DFPP-DG is a very potent PNP inhibitor with apparent inhibition constants (in the presence of 1 mM phosphate) of 4.

Inhibition of lipopolysaccharide-induced release of interleukin-8 from intestinal epithelial cells by SMA, a novel inhibitor of sphingomyelinase and its therapeutic effect on dextran sulphate sodium-induced colitis in mice.

Lipopolysaccharide (LPS) and inflammatory cytokines cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM) to produce a lipid messenger ceramide. The use of SMase inhibitors may offer new therapies for the treatment of the LPS- and cytokines-related inflammatory bowel disease (IBD). We synthesized a series of difluoromethylene analogues of SM (SMAs).

Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice.

Lipopolysaccharide (LPS) and inflammatory cytokines cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM) to produce a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related inflammatory bowel disease. We synthesized a series of difluoromethylene analogues of SM (SMAs).

Properties and application of oligodeoxynucleotides containing the naphthyridine:imidazopyridopyrimidine base pairs with the ability to form four hydrogen bonds.

As our continuing study to develop base pairing motifs which stabilize and regulate DNA structure, we designed novel 1,8-naphthyridine C-nucleosides possessing Na-O(N) and Na-N(O) bases. These C-nucleosides formed two sets of naphthyridine:imidazopyridopyrimidine base pairing motifs (Na-O(N):Im-N(O) and Na-N(O):Im-O(N)) with four hydrogen bonds, and duplexes containing the pairs were markedly thermally stabilized independent of the manner in which the new pairs are incorporated.

Synthesis and characterization of oligodeoxynucleotides containing naphthyridine:imidazopyridopyrimidine base pairs at their sticky ends. Application as thermally stabilized decoy molecules.

We describe the synthesis and properties of oligodeoxynucleotides (ODNs) containing 1,8-naphthyridine C-nucleoside (Na-NO) and imidazo[5',4':4,5]pyrido[2,3-d]pyrimidine nucleoside (Im-ON) at the termini. The modified ODNs were more resistant (6 to 40 times) than natural DNA to snake venom phosphodiesterase (SVPD). Although incorporation of one pair each of Na-NO:Im-ON on the sticky ends of the duplex was insufficient for thermal stabilization (+2.

Synthesis and biological evaluation of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine derivatives for PNP-inhibitors.

9-(5',5'-Difluoro-5'-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of alpha-methyl and beta-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (+/-)-4.

Synthesis and properties of oligodeoxyribonucleotides containing the new base pairs, Im-N(O):Na-O(N) and Im-O(N):Na-N(O), with the ability to form four hydrogen bonds.

Previously, we synthesized oligodeoxyribonucleotides (ODNs) containing novel base pairing motif consisting of tricyclic nucleosides, Im-N(O) and Im-O(N), with the ability to form four hydrogen bonds (H-bonds). When the base pair, Im-N(O):Im-O(N) pair, was incorporated into the duplex, thermal stability of the duplex depended on the sequence context. In this time, on the basis of previous results, we designed two new bicyclic nucleosides, Na-N(O) and Na-O(N) as complementary nucleobase of the tricyclic nucleobases.

New base pairing motifs. The synthesis and thermal stability of oligodeoxynucleotides containing imidazopyridopyrimidine nucleosides with the ability to form four hydrogen bonds.

The synthesis and thermal stability of oligodeoxynucleotides (ODNs) containing imidazo[5',4':4,5]pyrido[2,3-d]pyrimidine nucleosides 1-4 (N(N), O(O), N(O), and O(N), respectively) with the aim of developing two sets of new base pairing motifs consisting of four hydrogen bonds (H-bonds) is described. The proposed four tricyclic nucleosides 1-4 were synthesized through the Stille coupling reaction of a 5-iodoimidazole nucleoside with an appropriate 5-stannylpyrimidine derivative, followed by an intramolecular cyclization. These nucleosides were incorporated into ODNs to investigate the H-bonding ability.