J. Med. Chem.
2292
1989,32, 2292-2296
Retinobenzoic Acids. 4. Conformation of Aromatic Amides with Retinoidal Activity. Importance of trans -Amide Structure for the Activity Hiroyuki Kagechika, Toshiyuki Himi, Emiko Kawachi, and Koichi Shudo* Faculty of Pharmaceutical Scienoes, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. Received January 3, 1989 N-Methylation of two retinoidal amide compounds, 4- [ (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (3, Am80)and 4- [ [ (5,6,7,8tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)~~nyl]amino]benzoic acid (5, Am.5801,resulted in the disappearance of their potent differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. Studies with 'H NMR and UV spectroscopy indicated that large conformational differences exist between the active secondary amides and the inactive N-methyl amides. From a comparison of the spectroscopic results of these amides with those of stilbene derivatives, the conformations of the active amides are expected to resemble that of (E)-stilbene, whereas the inactive amides resemble the 2 isomer: 3 (Am80) and 5 (Am580) have a trans-amide bond and their whole structures are elongated, while the N-methylated compounds [4 (Am90) and 6 (Am590)I have a cis-amide bond, resulting in the folding of the two benzene rings. These structures in the crystals were related to those in solution by 13C NMR spectroscopic comparison between the two phases (solid and solution). Chart I Retinobenzoic acids are defined as "a series of benzoic acid derivatives with potent retinoidal activities ( t h a t is, the specific activities of retinoic acid)".'P2 T h e y modulate the cellular differentiation and proliferation in many types of cells in the cases where retinoic acid (1) acts as a m o d u l a t ~ r . ~Their , ~ mechanism of action seems to be the same as that of retinoic a ~ i dand , ~ since ~ ~ t h e y probably also bind to the same receptor,' t h e y are biologically classified as "retinoids" (Chart In the generic chemical structure of retinobenzoic acids, represented by 2, R is a medium-sized alkyl group(s), such as isopropyl or tert-butyl, In particular, a m-alkyl g r o u p is necessary for the activity. Another g r o u p required is the carboxyl trans, group at the para position of the other benzene ring. The linking g r o u p X can be varied, such as -NHCO-,9 --CONH-,'O -SO,NH-, -COC=C-," -N=N--" and so on. Among synthesized retinobenzoic acids, two types of benzanilides, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthaleny1)carbamoyllbenzoic acid acid (3, 3 (Am80) Am80) and 4-[ [ (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthalenyl)carbonyl]amino]benzoic acid (5, Am580), showed very strong retinoidal activities in several assay systems.' For example, 3 (Am801 and 5 (Am580) are several times more active than retinoic acid in terms of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60 (Table I). However, in the course of studies of the structure-activity relationships of these
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5 (Am580)
,-Ah,
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4 (Am90)
Kagechika. H.: Kawachi. E.: Hashimoto.. Y.:, Himi., T.:, Shudo. K. 3. Med: Chem. 1988,'31,' 2182. Sporn, M. B.; Roberts, A. B.; Goodman, D. S., Eds. The Retinoids; Academic Press, Inc.: Orlando, FL 1984. Sporn, M. B.; Roberts, A. B.; Roche, N. S.; Kagechika, H.; Shudo, K. J. Am. Acad. Dermatol. 1986, 15, 756. Jetten, A. M.; Anderson, K.; Deas, M. A.; Kagechika, H.; Lotan, R.; Rearick, J. I.; Shudo, K. Cancer Res. 1987, 47, 3523. Hashimoto, Y.; Kagechika, H.; Kawachi, E.; Shudo, K. Chem. Pharm. Bull. 1987,35, 3190. Takagi, K.; Suganuma, M.; Kagechika, H.; Shudo, K.; Ninomiya, M.; Muto, Y.; Fujiki, H. J. Cancer Res. Clin. Oncol. 1988, 114, 221.
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6 (Am590)
Table I. Differentiation-Inducing Activities of Retinoidal Amide Compounds on HL-60 Cells compd EDw, M rel. act.C retinoic acid 2.4 X 10+ 100 3 (Am80)O 7.9 x 10-10 350 4 (Am90)O >load 300 "C; lH NMR (100 MHz, DMSO-d6) 1.33 (s, 12 H), 1.71 (s, 4 H), 4.98 (s, 2 H), 7.63 (s, 1 H), 7.72 (s, 1H), 8.01 (s, 4 H). Anal. (C23H25N03) C, H, N.
amino)methane (3.6 mL, 20.8 mmol) was added to a solution of 1,2,3,4-tetrahydro-l,1,4,4,6-pentamethyl-7-nitronaphthalene (2.85 g, 11.5 mmol) in 30 mL of DMF under Ar gas, and the mixture was heated a t 115 "C for 24 h. The mixture was cooled to room temperature, and then semicarbazide hydrochloride (8.5 g, 76.2 mmol) in 15 mL of H 2 0 was added to the solution. After 20 min, the precipitates were collected and dissolved in CH2C12. The organic layer was washed with H 2 0 and dried over MgSOk After evaporation, the crude product was recrystallized from CH30H t o give 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-nitro- Acknowledgment. We are very grateful to JEOL Ltd. for the measurement of the solid-state NMR spectra. naphthalen-2-y1)ethanal semicarbazone (99% ). The semiRegistry No. 3,94497-51-5; 4, 110383-33-0; 5, 102121-60-8; carbazone (1.5 g, 4.86 mmol) was dissolved in CH30H and hy6, 116193-58-9; 7,119454-82-9; 8, 121866-06-6; 12, 121866-07-7; drogenated on 10% Pd-C (1.0 g) to give 5,6,7,8-tetrahydro12 benzyl ester, 121866-12-4; 13,121866-08-8; 13 methyl ester, 5,5,8,8-tetramethyl-lH-benzMindole (quant. yield). Next, 65 mg 121866-14-6;14, 121866-09-9; 14 methyl ester, 121866-17-9;c6of NaH (60% purity, 1.63 mmol) was washed twice with n-hexane HSCH2OCOC6H4-4-COC1, 67852-95-3; CH30COCeH4-4-COC1, and suspended in 30 mL of dry DMF. The indole (327 mg, 1.44 7377-26-6; C2H50COCsH4-4-NH,, 94-09-7; 1,2,3,4-tetrahydrommol) was added and the mixture was stirred for 1 h. Tere1,1,4,4,6-pentamethyl-7-nitronaphthalene, 116233-16-0; 2phthalic acid monobenzyl ester chloride was added to this solution (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-nitronaphthalen-2-y1)a t 0 "C and the mixture was stirred for 3 h. The solvent was ethanal semicarbazone, 121866-10-2; 5,6,7,8-tetrahydro-5,5,8,8removed under vacuum and the residue was diluted with AcOEt tetramethyl-lH-benz[flindole,121866-11-3; 2,3,5,6,7,8-hexaand H20. The organic layer was washed with water and brine hydro-5,5,8,8-tetramethyl-lH-benzVJindole, 121866-13-5; methyl and dried over MgS04. After evaporation, the residue was 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthoate, 121866chromatographed on silica gel to give benzyl 4-[(5,6,7,8-tetrahydro-5,5,8,&tetramethyl-lH-benzlflindol-l-yl)~~nyl]benz~te 15-7; methyl 3-(bromomethyl)-5,6,7,8-tetrahydro-5,5,8,8-tetra(43.9%). This benzyl ester (97 mg,0.208 mmol) was hydrogenated methyl-2-naphthoate, 121866-16-8.
