Synthesis of Halogen-Substituted Pyridyl and Pyrimidyl Derivatives of [3,2-c]Pyrazolo Corticosteroids:  Strategies for the Development of Glucocorticoid Receptor Mediated Imaging Agents

Abstract

Ligands for the glucocorticoid receptor labeled with high-energy isotopes are highly desired for their potential applications in nuclear medical studies of the brain where the dysregulation of this receptor system is thought to be involved in various neurodegenerative disorders. Analogues of the glucocorticoid cortivazol have previously been prepared as target compounds for labeling with high-energy isotopes. However, the phenyl rings of arylpyrazoles of this type are not sufficiently activated for nucleophilic substitution reactions that are generally required for the synthesis of radiohalogenated analogues. Since suitably substituted aromatic nitrogen heterocyclic groups are amenable to nucleophilic substitution, the goal of this study was the synthesis of pyridylpyrazolo and pyrimidylpyrazolo analogues similar to cortivazol that could be labeled with radiohalogens in the pyridine or pyrimidine rings. We describe the synthesis of several [3,2-c]pyrazolo steroids containing pyridyl, halopyridyl, and pyrimidyl substituents at the 2' position of the pyrazole ring. These compounds were tested for binding to the glucocorticoid receptor and for biological activity in glucocorticoid responsive HeLa cells grown in tissue culture. Of the pyridyl and pyrimidyl derivatives, 2'-(3-pyridyl)-11 beta,17,21-trihydroxy-16 alpha-methyl-20-oxopregn-4-eno[3,2-c]pyrazole showed superior activity in both assays and it was used as the basis for the synthesis of several analogues that were halogenated in the pyridine ring. These halogenated compounds were all tested for their binding to the glucocorticoid receptor and for their biological activity. One, a fluorinated compound 2'-(2-fluoro-5-pyridyl)-11 beta,17,21-trihydroxy-16 alpha-methyl-20-oxopregn-4-eno[3,2-c]pyrazole had excellent activity, considerably better than the potent glucocorticoid dexamethasone. Most importantly, fluorination was achieved using a nucleophilic exchange reaction, a method that is adaptable to radiolabeling with the positron-emitting isotope fluorine-18. Thus, considering its superior biological activity and adaptability for facile radiosynthesis, this target compound has the potential for imaging of glucocorticoid receptor containing tissues using positron emission tomography.

Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive

“…Accordingly, COS-1 cells were transfected with the YFP-hGR␤ expression plasmid, treated with various ligands, and then observed live using fluorescence microscopy for nuclear localization of YFPhGR␤ (Table 1). Several classes of ligands were examined, including 10 glucocorticoids; four antiglucocorticoids; six analogs of cortivasol (14,15); and ligands for the estrogen, progesterone, and androgen receptors. In addition, 37 antiprogestins with structural similarities to RU-486 were also tested (26,35).…”

“…Four of the potential hGR␤ ligands that were experimentally evaluated (dexamethasone, RU-486, RTI 6413-001, and ZK98299) were successfully computationally docked into the hGR␤ binding site. Figure 6A illustrates the highest score pose and conformation for each of the four ligands docked into the hGR␤ model struc- (14) No ND 11 (14) No ND 12 (14) No ND 16b (15) No ND ture. All docked poses and conformations of the dexamethasone ligand had significantly lower docked GlideScores than did the other three ligands and significantly higher total energy values for the ligand and receptor combined (data not shown).…”

Synthesis of Fullerene Adducts with Terpyridyl‐ or Pyridylpyrrolidine Groups in trans‐1 Positions

“…Terpyridylglycine was eventually synthesized in 73 % yield by treating ATP with ethyl glyoxylate and concentrated HCl followed by reductive hydrogenation. [27] The characterization of terpyridylglycine was established on the basis of MALDI-TOF mass spectrometry, and 1 H, 13 C, and COSY NMR spectroscopy (see the Supporting Information).…”

Evaluation of Anti‐inflammatory, Anti‐nociceptive, and Anti‐ulcerogenic Activities of Novel Synthesized Thiazolyl and Pyrrolyl Steroids

“…Moreover, the biological properties of modified steroids have proved to be of interest [4][5][6]. There has been considerable interest in the synthesis and biological study of several heterocyclic steroids as high potent anti-inflammatory agents [7][8][9]. The incorporation of an azole ring to the 2,3-positions of various steroids was effective in the production of a variety of compounds possessing anti-inflammatory proper-ties [10,11].…”