Hiroshi Kogen

A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.

Alzheimers disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).

A novel β-sheet breaker, RS-0406, reverses amyloid β-induced cytotoxicity and impairment of long-term potentiation in vitro

Fibril formation of amyloid β peptide (Aβ) is considered to be responsible for the pathology of Alzheimers disease (AD). The Aβ fibril is formed by a protein misfolding process in which intermolecular β‐sheet interactions become stabilized abnormally. Thus, to develop potential anti‐AD drugs, we screened an in‐house library to find compounds which have a profile as a β‐sheet breaker. We searched for a β‐sheet breaker profile in an in‐house library of approximately 113,000 compounds. From among the screening hits, we focused on N,N′‐bis(3‐hydroxyphenyl)pyridazine‐3,6‐diamine (named RS‐0406), which had been newly synthesized in our laboratory. This compound (10–100 μg ml−1) was found to be capable of significantly inhibiting 25 μM Aβ1–42 fibrillogenesis and, furthermore, disassembling preformed Aβ1–42 fibrils in vitro. We then investigated the effect of RS‐0406 on 111 nM Aβ1–42‐induced cytotoxicity in primary hippocampal neurons, and found that 0.3–3 μg ml−1 RS‐0406 ameliorates the cytotoxicity. Moreover, 3 μg ml−1 RS‐0406 reversed 1 μM Aβ1–42‐induced impairment of long‐term potentiation in hippocampal slices. In this study, we have succeeded in identifying RS‐0406 which has potential to inhibit Aβ1–42 fibrillogenesis, and to protect neurons against Aβ1–42‐induced biological toxicity in vitro. These results suggest that RS‐0406 or one of the derivatives could become a therapeutic agent for AD patients.

Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.

We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimers disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration.

A Highly Stereoselective Synthesis of (E)-α-Bromoacrylates

Abstract Novel reagent, methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate (5a), was designed and prepared in order to efficiently synthesize (E)-α-bromoacrylates 7, from which widely useful precursors for various C–C bond formations were prepared. Horner–Wadsworth–Emmons (HWE) reaction of various aldehydes with 5a in the presence of t-BuOK and 18-C-6 gave corresponding (E)-α-bromoacrylate derivatives with high stereoselectivity and excellent yield. Using the product (E)-α-bromoacrylate 7s as a key intermediate, we succeeded in developing the most effective route of plaunotol synthesis via Suzuki cross-coupling.

Asymmetric total synthesis of epolactaene. Part 2: Introduction of the side chain and synthesis of (+)-epolactaene and its enantiomer☆

Abstract A total synthesis of the novel neuritogenic agent (+)-epolactaene ((+)- 1 ) has been achieved via a convergent route that utilized epoxyamide 8 , C7–C11 fragment 7 , and C1–C6 Wittig reagent derived from phosphonium salt 19 followed by cyclization to form the lactam. The absolute configuration of natural epolactaene is definitively established as (13 R , 14 R ). Synthesis of (−)- 1 , the enantiomer of this natural epolactaene, is also described.

A highly stereoselective synthesis of plaunotol and its thiourea derivatives as potent antibacterial agents against Helicobacter pylori.

Practical and highly stereoselective synthesis of diterpene alcohol, plaunotol (1) and its thiourea derivatives 2a, 3a and 4a, via Z-selective Wittig reaction between alpha-acetal ketone 5 and phosphonium salt 6 and their antibacterial activity against Helicobacter pylori are described.

Asymmetric total synthesis of epolactaene. Part 1: Construction of epoxy-γ-lactam moiety and deduction of absolute stereochemistry

Abstract Enantioselective construction of the epoxy-γ-lactam moiety of epolactaene (1) was completed in 11 steps from (R)-lactaldehyde derivatives. Key steps include: (i) the stereoselective aldol reaction between (R)-lactaldehyde and malonate ester; (ii) diastereospecific lactonization of malonate ester derivative 10; (iii) cyclization of 16 to epoxy-γ-lactam derivative 2. Both enantiomers, (R,R)- 2 and (S,S)- 2 , were synthesized, and their optical rotations were compared with that of (+)-epolactaene (1). The results suggest that the absolute configuration of 1 is (13R,14R).

Total synthesis and NMR conformational study of signal peptidase II inhibitors, globomycin and SF-1902 A5

Abstract A stereoselective total synthesis of an antibiotic, globomycin ( 1a ), and its congener, SF-1902 A5 ( 1b ), was achieved. Two convergent macrocyclization routes via macrolactamization or macrolactonization to form 1a are described. A conformational study by means of NMR spectroscopy was performed in several solvents. The 1H NMR spectrum of 1a indicated that the amide proton of only the l -allo-Thr residue was involved in the hydrogen bonding. The structure in solution phase was different from the X-ray structure.

Synthesis and antimicrobial activity of novel globomycin analogues.

Globomycin, a signal peptidase II inhibitor, and its derivatives show potent antibacterial activity against Gram-negative bacteria. The synthesis and antimicrobial activity of novel globomycin analogues are reported. One of the analogues showed a more potent activity against Gram-negative bacteria than globomycin and also exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

Synthesis of Plaunotol Derivatives and their Antibacterial Activities against Helicobacter pylori

Plaunotol, a known antiulcer drug, has antibacterial activities against Helicobacter pylori. Plaunotol thiourea derivatives 2--4 and diol derivatives 6--10 were designed in search for a compound with high antibacterial activities. Thiourea derivatives 2--4 were synthesized regioselectively using our effective synthetic route for plaunotol (1), and diol derivatives 6--10 were also synthesized. Their antibacterial activities against H. pylori are described and we found that the most potent antibacterial agent was C1-thiourea derivative 2c.