ABSTRACT
A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent.
Subject(s)
Antineoplastic Agents/pharmacology , Azepines/pharmacology , CD28 Antigens/metabolism , Drug Discovery , Immunosuppressive Agents/pharmacology , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Azepines/chemical synthesis , Azepines/chemistry , CD28 Antigens/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Acetyltransferases , Histone Chaperones , Humans , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Molecular Structure , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/metabolism , Phenotype , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
A method for enantioselective desymmetrization of N-Ac and N-Boc-FTY720 by nonenzymatic asymmetric acylation was developed. Effective enantioselective monobenzoylation using benzoyl chloride in the presence of the tetraphenylbisoxazoline (L2)-CuCl2 complex gave the desired products 3a and 3b in 52-62% yield with 64% ee.
Subject(s)
Propylene Glycols/chemistry , Sphingosine/analogs & derivatives , Acylation , Benzoates/chemistry , Catalysis , Coordination Complexes/chemistry , Copper/chemistry , Fingolimod Hydrochloride , Oxazoles/chemistry , Solvents/chemistry , Sphingosine/chemistry , StereoisomerismABSTRACT
A concise synthesis of a useful intermediate 10 for the preparation of fingolimod (FTY-720) analogs was achieved by utilizing a chemoselective Sonogashira reaction of trihalobenzene 12 with alkyne 13. The reaction proceeded with high selectivity to give alkyne 11 containing the dihalobenzene moiety in good yield. Compound 11 was converted into intermediate 10 by hydrogenation without reduction of the halogen atoms.
Subject(s)
Immunosuppressive Agents/chemistry , Propylene Glycols/chemistry , Sphingosine/analogs & derivatives , Alkynes/chemical synthesis , Alkynes/chemistry , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Catalysis , Fingolimod Hydrochloride , Immunosuppressive Agents/chemical synthesis , Palladium/chemistry , Propylene Glycols/chemical synthesis , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistryABSTRACT
A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P(1)) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P(1) but no agonism at S1P(3), which had been reported to be a receptor responsible for heart rate reduction. Although high S1P(1)/S1P(3) selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P(3) agonism should be responsible for the heart rate reduction caused by S1P(1) agonists. Only 2-amino-2-[2-[2'-fluoro-4'-(4-methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P(1) receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.
