Yukio Tada

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound.

Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Remarkable kinetic solvent isotope effect on the cycloaromatization of C-1027 chromophore, a 9-membered enediyne, and the thermochemistry

Abstract Remarkable kinetic solvent isotope effect, experimental activation energy (15.1 kcal/mol) as well as MO calculations present a reaction energy diagram for cycloaromatization reaction of C-1027 chromophore, a highly strained 1,5-diyn-3-ene molecule.

Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists.

Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2.

Selective CB2 agonists with anti-pruritic activity: Discovery of potent and orally available bicyclic 2-pyridones

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.

Reactions of azathiabenzene anion with electrophiles. Formation and x-ray analysis of novel heterocyclic compounds from the reaction with carboxylic ester

Abstract The anion (2) generated from 9-methyl-10-aza-9-thiaphenanthrene (1) reacted with carboxylic ester to give the spiro compounds (9a), (9b) via Sommelet-Hauser rearrangement, whose structures have been confirmed by an X-ray crystal structure determination of (9a).

Reactions of 9-substituted 9-thia-10-azaphenanthrenes with electrophiles

Reactions of 9-substituted 9-thia-10-azaphenanthrenes with several electrophiles have been investigated. Reaction of 9-alkyl-9-thia-10-azaphenanthrenes with dimethyl acetylenedicarboxylate (DMAD) afforded dibenzothiazonine derivatives 4 and 5, dibenzothiazocine derivatives 6, 2-alkylsulfinyl-2′-vinylaminobiphenyls 7, and bis(biphenylylimino)ethane derivatives 8. The product distribution was markedly influenced by the substituent on the sulfur atom. 9-Methyl 3a and 9-isopropyl derivatives 3d afforded predominantly dibenzothiazonine derivatives 5a and 4d, respectively, while 9-ethyl 3b, 9-isopropyl 3c and 9-cyclohexyl derivatives 3e gave predominantly dibenzothiazocine derivatives 6 and alkylsulfinyl vinylaminobiphenyls 7. In contrast, the reactions of 9-phenyl-3f or 9-vinyl-9-thia-10-azaphenanthrene 3g with DMAD afforded only the corresponding dibenzothiazocine derivative 6. Reactions of 9-alkylthiaazaphenanthrenes 3a–c with methyl propiolate (MP) in benzene afforded dibenzothiazecine derivatives 12 as 1:2 adducts. Reactions of compounds 3a–c with diphenylcyclopropenone in ethanol yielded the ring-opened products 13, while the same reaction in benzene solvent afforded the 4-quinolone derivatives 14via intramolecular cyclization of a ketene intermediate, L.