Synthesis and Structure−Activity Relationships of 2-Pyrazinylcarboxamido- benzoates and β-Ionylideneacetamidobenzoates with Retinoidal Activity

Abstract

The structure-activity relationships of two series of novel retinoids (2-pyrazinylcarboxamidobenzoates and beta-ionylideneacetamidobenzoates) have been investigated by evaluating their ability to induce differentiation in both human promyelocytic leukemia (HL60) cells and mouse embryonal carcinoma (P19) cells. The most active compound (ED50 = 8.3 x 10(-9) M) of the 2-pyrazinylcarboxamidobenzoates is 4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethylquinoxalyl)carboxamido]benzoic acid (9u), while the most active analogue of the beta-ionylideneacetamidobenzoates is 4-[3-methyl-5-(2',6',6'-trimethyl-1'-cyclohexen-1'-yl)-(2E, 4E)-pentadienamido]benzoic acid (10a, ED50 = 3.2 x 10(-8) M). Our studies identify an absolute requirement for the carboxylic acid moiety on the aromatic ring to be para relative to the amide linkage for activity. Benzoate substitutions in the ortho position relative to the terminal carboxylate (9d,k,r) are well-tolerated; however, a methoxy substituent meta relative to the terminal carboxylate gives rise to only weakly active analogues (9x). Conformational studies (NMR, X-ray crystallography) of the 2-pyrazinylcarboxamidobenzoates indicate that the preferred conformation exhibits a trans-amide bond and an internal hydrogen bond between the quinoxaline N1 and HN amide which locks the torsional angle between C2 and CO in the s-trans conformation. N-Methylation (9y) results in loss of activity. Studies indicate that there is now a cis-amide bond present which redirects the carboxylate toward the pharmacophoric gem-dimethyl groups. The distance between the gem-dimethyl group and the terminal carboxylate appears to be too short to activate the retinoid receptor. N-Methylation in the beta-ionylideneacetamidobenzoate series (10c) also results in the formation of a cis-amide bond and loss of activity.

Interaction of 6,6′′-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2′:6′,2′′-terpyridine (CyMe4-BTTP) with some trivalent ions such as lanthanide(iii) ions and americium(iii)

“…13 Diethyl 2,2,5,5-tetramethylhexanedioate 11 was obtained by the dimerization of pivalic acid using Fenton's reagent, 14 followed by 35 esterification of 2,2,5,5-tetramethylhexanedioic acid with conc. sulfuric acid in ethanol.…”

“…sulfuric acid in ethanol. 11 2,2':6',2''-Terpyridine-6,6''-dicarbonitrile 15 6 was obtained by the oxidation of 2,2':6',2''-terpyridine with m-CPBA, 16 followed by modified ReissertHenze reaction with N,N-dimethylcarbamyl chloride and 40 trimethylsilyl cyanide in dichloromethane. 17 WARNING: trimethylsilyl cyanide is a volatile hydrogen cyanide equivalent.…”

Complexation of lanthanides, actinides and transition metal cations with a 6-(1,2,4-triazin-3-yl)-2,2′:6′,2′′-terpyridine ligand: implications for actinide(iii)/lanthanide(iii) partitioning

“…A modified Reissert-Henze reaction 17 of 4 with trimethylsilyl cyanide and N,N-dimethylcarbamyl chloride afforded the nitrile 6 18 in high yield (CAUTION: trimethylsilyl cyanide is a volatile hydrogen cyanide equivalent). 30 The reaction of 6 with hydrazine hydrate gave the carbohydrazonamide 7 19 which, on treatment with 3,3,6,6-tetramethylcyclohexane-1,2-dione 8 20,21 in THF/Et 3 N at reflux furnished the ligand 2 in 93% yield (see Supporting Information for the synthesis of compounds 4-7). The X-ray crystal structure of 2 is shown in Figure 2 together with the atomic numbering scheme.…”

“…v max (Nujol ® )/cm −1 3082, 2967, 2933, 2869, 1596, 1570, 1525, 1455, 1426, 1388, 1344, 1247, 1184, 1165, 1146, 1053, 816, 778, 750, 721, 680, 644, 625, 541. 8.28 (qu,J 4.1,ArH minor),8.33 (dd,J 7.7 4 (0.0297 g, 1 eq) in CH 3 CN (4 mL). The two solutions were mixed and the solvents were allowed to evaporate over several days to 20 afford the complex as a light brown solid (0.0488 g, 95 %). Mp >300 o C (from DCM/MeCN).…”

“…We also thank the EPSRC and the University of 20 Reading for funds for the X-Calibur system. Use of the Chemical Analysis Facility at the University of Reading is gratefully acknowledged.…”