Synthesis and biological activity of carboxyl-terminus modified prostaglandin analogs

Abstract

A series of PGE2, 16,16-dimethyl-PGE2, and PGF2 alpha analogues modified at the carboxyl terminus with tetrazole, amide, acylurea, imide, and sulfonimide functionalities was evaluated for uterine stimulant, bronchodilator, hypotensive, gastric antisecretory, and diarrheal activity. These compounds were prepared by modification of the Corey prostaglandin synthesis utilizing as a key step condensation of known hemiacetals with the ylide derived from the requisite substituted phosphonium salts. Structure--activity relationships suggest that a proton at the C-1 position appears necessary for agonist activity and the acidity of this proton has a relatively greater influence on activity than pendant steric bulk. Noteworthy are the tissue-selective bronchodilator activity of N-acetyl-PGE2-carboxamide and the selectivity for uterine tissue of N-methanesulfonyl-PGE2-carboxamide, 2-decarboxy-2-(tetrazol-5-yl)-16,16-dimethyl-PGE2, N-acetyl-16,16-dimethyl-PGE2-carboxamide, and N-methanesulfonyl-16,16-dimethyl-PGE2-carboxamide.

Key Structural Features of Prostaglandin E2and Prostanoid Analogs Involved in Binding and Activation of the Human EP1Prostanoid Receptor

“…This ability to retain potency is, therefore, probably attributable to the presence of a phenoxy substitution at the C-16 position on both structures (see below and Table 5). It has also been suggested, in a prior study using a series of C-1 modified PGE 2 analogs tested in several bioassay systems, that at the C-1 position, acidity is more important than steric bulk for activity (Schaaf and Hess, 1979). This may also contribute to the potency of sulprostone (13) at hEP 1 .…”

Effects of Acetylenic Epoxygenase Inhibitors on Recombinant Cytochrome P450s

“…Conversion of the free carboxylic acid function of PPOH to the methylsulfonyl amide derivative (Fig. 1) was expected to confer resistance to ␤-oxidation (Schaaf and Hess, 1979;Wang et al, 1998), but resulting alterations in pharmacodynamic properties were not anticipated and have never been reported. The present studies show both strong similarities and notable differences between the effects of MS-PPOH and its parent drug.…”

“…However, PPOH and MS-PPOH have been used in vitro as selective P450 epoxygenase inhibitors not only in the kidney (Wang et al, 1998;Imig et al, 1999;Brand-Schieber et al, 2000) but also in astrocytes (Rzigalinski et al, 1999) and in pulmonary arteries (Zhu et al, 2000). MS-PPOH, a metabolically stable congener of PPOH (Schaaf and Hess, 1979;Wang et al, 1998), has been used both in vivo and in vitro to block renal (Brand-Schieber et al, 2000) and brain (Bhardwaj et al, 2000;Peng et al, 2002;Conroy et al, 2010) epoxygenases. Thus, PPOH and MS-PPOH have been used to target P450 epoxygenases throughout the body, but the P450 isoforms responsible for the extrarenal actions of these drugs are unknown.…”

Photochemistry and Vibrational Spectra of Matrix-Isolated 5-Ethoxy-1-Phenyl-1H-Tetrazole

“…43 Results and Discussion DFT Structural Calculations: Molecular Geometry. The molecule of 5-ethoxy-1-phenyl-1H-tetrazole has three internal rotational degrees of freedom, defined about the -C (6) The dihedral angle around the C (6) -N (1) bond defines the relative orientation of the phenyl and tetrazole rings. Calculations show that in all conformers these two rings have approximately planar geometries.…”

“…In 5-methoxy-1-phenyltetrazole 29 the equivalent vibration absorbs as a site-split doublet at 1572.3 and 1571.3 cm -1 . The νC-N vibration (associated with the C (5) -N (1) bond) gives rise to a doublet at 1453.0/1447.5 cm -1 , while that ascribable to the νN-C coordinate (associated with the N (1) -C (6) inter-ring bond) is observed as a doublet at 1299.4/1297.6 cm -1 (Table 1). According to the results of normal-mode analysis (see Table S3), these coordinates are somewhat coupled with the νNdC coordinate (especially νN-C), which may justify their relatively high frequency.…”