ABSTRACT
Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1ß, TNFα, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNFα production inhibitor in vitro but suffered from poor oral bioavailability. Structural modification of 2a led to the discovery of tetrahydropyrazolopyrimidine derivatives, exemplified by compound 3, with an improved pharmacokinetic profile. We found that blocking metabolism at the methyl group of the amine and constructing the tetrahydropyrimidine core were important to obtaining compounds with good biological profiles and oral bioavailability. Pursuing the structure-activity relationships of this series led to the discovery of AS1940477 (3f), with excellent cellular activity and a favorable pharmacokinetic profile. This compound represents a highly potent inhibitor of p38 MAP kinase with regard to in vivo activity in an adjuvant-induced arthritis model.
Subject(s)
Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Biological Availability , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokineticsABSTRACT
Various analogues of the marine alkaloids, discorhabdins, have been synthesized. The strategy contains spirocyclization with phenyliodine(III) bis(trifluoroacetate) (PIFA), oxidative fragmentation of the ß-amino alcohols with the hypervalent iodine reagent C(6)F(5)I(OCOCF(3))(2), the detosylation and dehydrogenation reaction of the pyrroloiminoquinone unit in the presence of a catalytic amount of NaN(3) and the bridged ether synthesis with HBr-AcOH as the key reactions. All the synthesized compounds were evaluated by in vitro MTT assay for cytotoxic activity against the human colon cancer cell line HCT-116. Furthermore, the discorhabdin A oxa analogues were also evaluated against four kinds of tumor model cells, a human colon cancer cell line (WiDr), a human prostate cancer cell line (DU-145) and murine leukemia cell lines (P388 and L1210). For the identification of the target, discorhabdin A and the discorhabdin A oxa analogue were evaluated by an HCC panel assay. In the test, discorhabdins could have a novel mode of action with the tumor cells.
Subject(s)
Quinones/chemical synthesis , Thiazepines/chemical synthesis , Animals , Cell Line, Tumor , Cell Survival/drug effects , Humans , Mice , Mice, Inbred BALB C , Molecular Structure , Neoplasms/drug therapy , Quinones/pharmacology , Quinones/therapeutic use , Structure-Activity Relationship , Thiazepines/pharmacology , Thiazepines/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Discorhabdin A (1) exhibits a strong cytotoxic activity in vitro, but it is difficult to synthesize and handle due to the instability of its highly strained N,S-acetal structure. We then designed the analogues of discorhabdin A which also have strong cytotoxic activity and stability. The synthesis and examination of the biological activity of various types of stable discorhabdin A oxa analogues (2) were achieved.
Subject(s)
Alkaloids/chemical synthesis , Drug Screening Assays, Antitumor , Marine Biology , Oxytocin/analogs & derivatives , Quinones/chemical synthesis , Spiro Compounds/chemical synthesis , Thiazepines/chemical synthesis , Acetals , Alkaloids/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Oxytocin/chemical synthesis , Oxytocin/chemistry , Quinones/chemistry , Quinones/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Thiazepines/chemistry , Thiazepines/pharmacologyABSTRACT
Hypervalent iodine(III) reagents are readily available, easy to handle, and have a low toxicity and similar reactivities to those of heavy metal reagents, and hence they are used for various oxidative reactions. The oxidative cleavage of alkynes or carbonyl compounds by using bis(trifluoroacetoxy)iodo(III) pentafluorobenzene (C(6)F(5)I(OCOCF(3))(2)) has been reported. Herein, the efficient direct synthesis of N,O-acetal compounds as key intermediates of discorhabdin A, by the oxidative fragmentation reaction of alpha-amino acids or beta-amino alcohols by using C(6)F(5)I(OCOCF(3))(2), is described.
Subject(s)
Amino Acids/chemistry , Amino Alcohols/chemistry , Hydrocarbons, Halogenated/chemistry , Quinones/chemical synthesis , Spiro Compounds/chemical synthesis , Thiazepines/chemical synthesis , CatalysisABSTRACT
The use of hypervalent iodine(III) reagents allowed us to develop the novel and efficient direct synthesis of N,O-acetal compounds via the oxidative fragmentation reaction of alpha-amino acids or alpha-amino alcohols; furthermore, we succeeded in developing an improved synthesis of the key intermediate of discorhabdins.
Subject(s)
Acetals/chemistry , Iodine Compounds/chemical synthesis , Nitrogen/chemistry , Oxygen/chemistry , Quinones/chemistry , Amino Alcohols/chemistry , Iodine Compounds/chemistry , Molecular Structure , Oxidation-Reduction , Quinones/chemical synthesis , Serine/analogs & derivatives , Serine/chemistryABSTRACT
The first stereoselective total synthesis of a potent antitumor alkaloid, discorhabdin A (1), which is a unique sulfur-containing pyrroloiminoquinone alkaloid, is described. The key step in the stereocontrolled total synthesis of 1 involves both a diastereoselective oxidative spirocyclization using a hypervalent iodine(III) reagent and an efficient construction of the labile and highly strained N,S-acetal skeleton. These methodologies provide a breakthrough in the total syntheses of these promising new antitumor agents, discorhabdins and their analogues, which should serve as valuable probes for structure-activity studies.
