Synthesis of structural analogs of leukotriene B4 and their receptor binding activity

Abstract

Structural analogs of leukotriene B4 (LTB4) were designed using a preferred conformation of LTB4 (1). Appending an aromatic ring scaffold between LTB4 carbons 7 and 11 led to quinoline analogs 3 and 15. A similar modification to the LTB4 structure between carbons 7 and 9 led to the pyridine analogs 41 and 46. The compounds of this study were evaluated in receptor binding assays using [3H]LTB4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline 3, displayed moderate potency in the LTB4 receptor binding assay (Ki = 0.9 microM). Modification of 3 by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, Ki = 0.01 microM); a further improvement in receptor binding was achieved in the pyridine series (e.g., 41; Ki = 0.001 microM). The LTB4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB4. Of the analogs prepared in this report only 47 demonstrated LTB4 receptor antagonist activity.

Epothilone Analogues with Benzimidazole and Quinoline Side Chains: Chemical Synthesis, Antiproliferative Activity, and Interactions with Tubulin

“…[25] The latter would be obtained from aldehydes I-4 by stereoselective aldol or allylation reactions. Scheme 2 summarizes the synthesis of vinyl iodide 12 as the requisite C13-C15 building block for the elaboration of analogues 1 a and 1 b. Oxidation of commercially available 7-methylquinoline (6) with SeO 2 gave quinoline-7-carboxaldehyde (7), [26] which was then submitted to aldol reaction with the boron-enolate of the acetylated Oppolzer sultam 8. [27,28] The aldol product 9 was obtained in 80 % yield as a 5:1 mixture of isomers, which were not separated, but directly converted to the corresponding C15-O-TBS ethers (epothilone numbering).…”

(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic Acid and Related Compounds: High Affinity Leukotriene B4 Receptor Antagonists

“…The residue was diluted with EtO, washed with 5% HCl, HzO, NaHC03, and brine, and dried (MgS04). Purification by flash column chromatography (2% EtOAc in hexane) gave 30 g (93%) of 14 as an orange oil: IH NMR (250 MHz, CDCl3) 6 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), (16). Alkyne 14 (30 g, 63.7 mmol) was dissolved in EtOH (125 mL) and EtOAc (125 mL) and treated with 5% Pd-C catalyst (3 g).…”

“…The LTB4 receptor antagonists of this study were prepared according to Schemes 1-5. The (p-methoxyphenyl)octyl iodide (16) was prepared as described in Scheme 1 starting from commercially available 3-octynl-ol (12). This was rearranged to the terminal acetylene The K¡ and IC50 values are stated as the mean of at least three determinations ± standard error.…”

“…The remaining solution was diluted with EtzO, washed with H2O and brine, and dried (MgS04). The solvent was removed, and the resulting residue was dissolved in CHzClz and applied to a flash chromatography column; elution with 2% EtOAc in hexane provided16.3 g (90%) of 16 as a colorless oil: lH NMR (250 MHz, CDC13) 6 7.08 (d, J = 8.6 Hz, 2H, aryl), 6.82 (d, J = 8.6 Hz, 2H, aryl), 3.78 (s, 3H, OCH3), 3.17 (t, J = 7.was stirred at room temperature for 6 h. The reaction mixture mixture was filtered through a pad of Celite, and the solvent was evaporated. Crude 21 was obtained as a tan solid and was used directly for the next step: IH NMR (250 MHz, CDC13) 6 10.65 (s, lH, OH), 10.30 (s, lH, aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl).…”

“…However, these initial compounds exhibited partial agonist activity. 16 An effort to reduce the structural similarity between these compounds and LTB4 led to a class of trisubstituted pyridines possessing moderate LTB4 receptor antagonist activity. However, more significantly, the compounds were found to be free of LTB4 agonist activity (e.g., •OH…”