[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
43
Acknowledgements Support of this work by U.S. Public Health Service Grants CA30512 and CA32428 is gratefully acknowledged.
[3] S t r u c t u r a l C h a r a c t e r i s t i c s o f S y n t h e t i c R e t i n o i d s
By BRAHMA P. SANI and DONALD L. HILL Introduction The word retinoid is a general term that includes both the naturally occurring compounds with vitamin A activity and the synthetic analogs of retinol, with or without biological activity. The I U P A C - I U B Joint Commission on Biochemical Nomenclature I states that "retinoids are a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. All retinoids may be formally derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion. To avoid confusion with previously used names in this field no parent hydrocarbon is named." The first total synthesis of a retinoid was reported by Kuhn and Morris in 1937. 2 Arens and Van Dorp reported the first synthesis of retinoic acid. 3 Isler e t al. 4 at Hoffmann-La Roche developed the first synthesis of retinol on an industrial scale. In this field, there have been major advances in synthetic organic chemistry, resulting in the synthesis of about 2000 retinoids. Some have little resemblance to retinol and retinoic acid but still retain the biological activities associated with them. Structures of Retinoids The classic retinoid structure is generally subdivided into three segments, namely, the polar terminal end, the conjugated side chain, and the cyclohexenyl ring. The basic structures of the most common natural retinoids are called retinol, retinaldehyde, and retinoic acid (Fig. 1). Structures of several derivatives of the naturally occurring retinoids and examples of typical synthetic retinoids are listed below. For many of these, 1 IUPAC-IUB Joint Commission on Biochemical Nomenclature, Eur. J. Biochem. 129, 1 (1982). 2 R. Kuhn and C. J. O. R. Morris, Chem. Ber. 70, 853 (1937). 3 j. F. Arens and D. A. Van Dorp, Nature (London) 175, 190 (1946). 4 0 . Isler, W. Huber, A. Ronco, and M. Kofter, Helo. Chim. Acta 30, 1911 (1947).
METHODS IN ENZYMOLOGY, VOL. 189
Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
44
[3]
STRUCTURE AND ANALYSIS 19
,7
I
18
3~ " , ~ 4
20 I
18
all-trans-Retinol; (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl- l-yl)-2,4,6,8-nonatetraen- l-ol
all-trans-Retinaldehyde; all-trans-retinal; hexen-l-yl)-2,4,6,8-nonatetmenal
(ali-E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclo-
~
OOH
all-trans-Retinoic acid; retinoic acid; (ail-E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen1-yl)-2,4,6,8-nonatetraenoic acid FIG. 1. Structure of retinol, retinaldehyde, and retinoic acid.
structure-activity relationships and chemical and physical properties have been reviewed at length. 5,6
1. all-trans-Retinyl ethers
~
CH20R
R = H, retinol
retinyl methyl ether retinyl butyl ether = C6H5, retinyl phenyl ether ---- C8H17, retinyl octyl ether = glucuronic acid, retinyl/3-glucuronide = CH3,
= C4H9,
5 D. L. Newton, W. R. Henderson, and M. B. Sporn, Cancer Res. 40, 3413 (1980). 6 F. Frickel, in "The Retinoids" (M. B. Sporn, A. B. Roberts, and D. S. Goodman, eds.), Vol. 1, p. 7. Academic Press, Orlando, Florida, 1984.
[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
2. all-trans-Retinyl esters
~
CH20R
R = COCH3, retinyl acetate = COC15H31, retinyl palmitate
3. all-trans-Retinylamine derivatives
~
CH2NRIR 2
R1, R2 = H, COCH3, N-acetylretinylamine = H , C O C 6 H 5 , N-benzoylretinylamine = CH3, COCH3, N-methyl-N-acetylretinylamine = CH3, COC6H5, N-methyl-N-benzoylretinylamine
4. all-trans-Retinal derivatives
~
R = = = = = = =
H=R
O, retinal N O H , retinal oxime N N H C O C H 3 , retinal acetylhydrazone C(COCH~CH2CH3)2, 5-retinylidene-4,6-nonanedione C(COCH2)2, 2-retinylidene-l,3-cyclopentanedione C(COCH2)2CH2, 2-retinylidene-l,3-cyclohexanedione C(COCH2CH2)zCHz, 2-retinylidene-l,3-cyclooctanedione
5. all-trans-Retinoic acid esters
~
R = = = =
H, retinoic acid CH3, ret~noic acid methyl ester C2H5, retinoic acid ethyl ester glucuronic acid, retinoyl fl-glucuronide.
COOR
45
46
STRUCTURE AND ANALYSIS
[3]
6. all-trans-Retinoylamino acids
R = = = =
glycine, retinoylglycine leucine, retinoylleucine phenylalanine, retinoylphenylalanine tyrosine, retinoyltyrosine
7. all-trans-retinamides
~
ONHR
R = C 2 H 5 , N-ethylretinamide = C3H7, N-propylretinamide = 2-C2H4OH, N-(2-hydroxyethyl)retinamide = 2-C3H6OH, N - ( 2 - h y d r o x y p r o p y l ) r e t i n a m i d e = 3-C3H6OH, N - ( 3 - h y d r o x y p r o p y l ) r e t i n a m i d e = C6H5, N - p h e n y l r e t i n a m i d e -- 2-C6H4OH, N-(2-hydroxyphenyl)retinamide = 4 - C 6 H 4 O H , N-(4-hydroxyphenyl)retinamide = 2-C6H4COOH, N-(2-carboxyphenyl)retinamide = 4-C6H4-COOH, N-(4-carboxyphenyl)retinamide
8. 5,6-all-trans-Epoxyretinoids
R = C O O H , 5,6-epoxyretinoic acid = C O O C H 3 , 5,6-epoxyretinoic acid methyl ester = C H 2 O C O C H 3 , 5,6-epoxyretinyl acetate . 13-cis-Retinoic acid derivatives
[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
R =
= = = = =
47
OH, 13-cis-retinoic acid NHC:Hs, N-ethyl-13-cis-retinamide NH(2-C2H4OH), N-(2-hydroxyethyl)-13-cis-retinamide NH(4-C6H4OH), N-(4-hydroxyphenyl)-13-cis-retinamide leucine, N-(13-cis-retinoyl)leucine phenylalanine, N-(13-cis-retinoyl)phenylalanine
10. Bifunctional retinoic acid analogs
RI, R2 = COOH, COOH, 14-carboxyretinoic acid ----- C O O C 2 H 5 , COOC2H5, ethyl 14-(ethoxycarbonyl)retinoate = CONHC2Hs, COOH, 14-[(ethylamino)carbonyl]-13-cisretinoic acid I 1.
Ring-modified all-trans-retinoic acid analogs
R~
O
O
H
R = [.~
a-retinoic acid
R = [~ IJ
= ~
,4-hydroxyretinoic acid
= [~ I~
C; ----CHsO ~
= ~]~,
phenyl analog of retinoic acid 4-methoxy' 2,3,6-trimethylphenyl analog of retinoic acid 5,6-dihydroretinoic acid
= [,. ]k. , 4-oxoretinoic acid
,3-pyridyl analog of retinoic acid , dimethylacetyl0ell5 cyclopentenyl analog of retinoic acid 2-furyi analog of retinoic acid
= ~
,3-thienyl analog of retinoic acid
48
STRUCTURE
AND
ANALYSIS
[3]
12. Side-chain-modified all-trans-retinoic acid analogs
R
=
.~OOH
, C~5 analog of retinoic acid
=
,,(~,..~'~C 00H
, C17
~ O O H ~~~C00H
, C22 analog of retinoic acid
= =
analog of retinoic acid
, aryltriene analog of retinoic acid
~/~~.~C
0OH
,7,8-dihydroretinoic acid
=
~~~./,C
00H
,9,10-dihydroretinoic acid
=
~ ~ ~ , C
00H
, I l, 12-dihydroretinoic acid
13. Ring- and side-chain-modified analogs of all-trans-retinoic acid
~
OOH
(E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyi-2-naphthalenyl)-lpropenyl]benzoic acid
~
OOH
(E)-4-[2-(5,6,7,8-Tetrahydro-8,8-dimethyl-2-naphthalenyl)-l-propenyl]benzoic acid
~
OOH
(E)-4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamolyl]benzoic acid
[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
~
49
OOH
(E)-4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid
~
OOH
(E)-4-[2-(2,3-Dihydro- 1,1,2,3,3-pentamethyl- I H-inden-5-yl)- 1-propenyl]benzoic acid
~
OOH
6-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid
~
~COOH
6-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-5-methyl2-naphthalenecarboxylic acid
2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-6-benzo[b] thiophenecarboxylic acid
50
STRUCTURE
~
[4]
AND ANALYSIS
.COOH
4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid
~
COOH
(E)-4-[3-(3,5-Di-tert-butylphenyl)-3-oxo-l-propenyl]benzoicacid
[4] H i g h - P e r f o r m a n c e Liquid C h r o m a t o g r a p h y o f R e t i n o i d s in Blood
By A. P. DE LEENHEER and H. J. NELIS Introduction
The principal form of vitamin A in blood under fasting conditions is retinol. ~This compound is mobilized from retinyl ester stores in the liver and circulates in association with its specific transport protein [retinolEG. A. J. Pitt, in "Fat-Soluble Vitamins--Their Biochemistry and Applications" (A. T. Diplock, ed.), p. 1. Heinemann, London, 1985.
METHODS IN ENZYMOLOGY, VOL. 189
Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
43
Acknowledgements Support of this work by U.S. Public Health Service Grants CA30512 and CA32428 is gratefully acknowledged.
[3] S t r u c t u r a l C h a r a c t e r i s t i c s o f S y n t h e t i c R e t i n o i d s
By BRAHMA P. SANI and DONALD L. HILL Introduction The word retinoid is a general term that includes both the naturally occurring compounds with vitamin A activity and the synthetic analogs of retinol, with or without biological activity. The I U P A C - I U B Joint Commission on Biochemical Nomenclature I states that "retinoids are a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. All retinoids may be formally derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion. To avoid confusion with previously used names in this field no parent hydrocarbon is named." The first total synthesis of a retinoid was reported by Kuhn and Morris in 1937. 2 Arens and Van Dorp reported the first synthesis of retinoic acid. 3 Isler e t al. 4 at Hoffmann-La Roche developed the first synthesis of retinol on an industrial scale. In this field, there have been major advances in synthetic organic chemistry, resulting in the synthesis of about 2000 retinoids. Some have little resemblance to retinol and retinoic acid but still retain the biological activities associated with them. Structures of Retinoids The classic retinoid structure is generally subdivided into three segments, namely, the polar terminal end, the conjugated side chain, and the cyclohexenyl ring. The basic structures of the most common natural retinoids are called retinol, retinaldehyde, and retinoic acid (Fig. 1). Structures of several derivatives of the naturally occurring retinoids and examples of typical synthetic retinoids are listed below. For many of these, 1 IUPAC-IUB Joint Commission on Biochemical Nomenclature, Eur. J. Biochem. 129, 1 (1982). 2 R. Kuhn and C. J. O. R. Morris, Chem. Ber. 70, 853 (1937). 3 j. F. Arens and D. A. Van Dorp, Nature (London) 175, 190 (1946). 4 0 . Isler, W. Huber, A. Ronco, and M. Kofter, Helo. Chim. Acta 30, 1911 (1947).
METHODS IN ENZYMOLOGY, VOL. 189
Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
44
[3]
STRUCTURE AND ANALYSIS 19
,7
I
18
3~ " , ~ 4
20 I
18
all-trans-Retinol; (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl- l-yl)-2,4,6,8-nonatetraen- l-ol
all-trans-Retinaldehyde; all-trans-retinal; hexen-l-yl)-2,4,6,8-nonatetmenal
(ali-E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclo-
~
OOH
all-trans-Retinoic acid; retinoic acid; (ail-E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen1-yl)-2,4,6,8-nonatetraenoic acid FIG. 1. Structure of retinol, retinaldehyde, and retinoic acid.
structure-activity relationships and chemical and physical properties have been reviewed at length. 5,6
1. all-trans-Retinyl ethers
~
CH20R
R = H, retinol
retinyl methyl ether retinyl butyl ether = C6H5, retinyl phenyl ether ---- C8H17, retinyl octyl ether = glucuronic acid, retinyl/3-glucuronide = CH3,
= C4H9,
5 D. L. Newton, W. R. Henderson, and M. B. Sporn, Cancer Res. 40, 3413 (1980). 6 F. Frickel, in "The Retinoids" (M. B. Sporn, A. B. Roberts, and D. S. Goodman, eds.), Vol. 1, p. 7. Academic Press, Orlando, Florida, 1984.
[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
2. all-trans-Retinyl esters
~
CH20R
R = COCH3, retinyl acetate = COC15H31, retinyl palmitate
3. all-trans-Retinylamine derivatives
~
CH2NRIR 2
R1, R2 = H, COCH3, N-acetylretinylamine = H , C O C 6 H 5 , N-benzoylretinylamine = CH3, COCH3, N-methyl-N-acetylretinylamine = CH3, COC6H5, N-methyl-N-benzoylretinylamine
4. all-trans-Retinal derivatives
~
R = = = = = = =
H=R
O, retinal N O H , retinal oxime N N H C O C H 3 , retinal acetylhydrazone C(COCH~CH2CH3)2, 5-retinylidene-4,6-nonanedione C(COCH2)2, 2-retinylidene-l,3-cyclopentanedione C(COCH2)2CH2, 2-retinylidene-l,3-cyclohexanedione C(COCH2CH2)zCHz, 2-retinylidene-l,3-cyclooctanedione
5. all-trans-Retinoic acid esters
~
R = = = =
H, retinoic acid CH3, ret~noic acid methyl ester C2H5, retinoic acid ethyl ester glucuronic acid, retinoyl fl-glucuronide.
COOR
45
46
STRUCTURE AND ANALYSIS
[3]
6. all-trans-Retinoylamino acids
R = = = =
glycine, retinoylglycine leucine, retinoylleucine phenylalanine, retinoylphenylalanine tyrosine, retinoyltyrosine
7. all-trans-retinamides
~
ONHR
R = C 2 H 5 , N-ethylretinamide = C3H7, N-propylretinamide = 2-C2H4OH, N-(2-hydroxyethyl)retinamide = 2-C3H6OH, N - ( 2 - h y d r o x y p r o p y l ) r e t i n a m i d e = 3-C3H6OH, N - ( 3 - h y d r o x y p r o p y l ) r e t i n a m i d e = C6H5, N - p h e n y l r e t i n a m i d e -- 2-C6H4OH, N-(2-hydroxyphenyl)retinamide = 4 - C 6 H 4 O H , N-(4-hydroxyphenyl)retinamide = 2-C6H4COOH, N-(2-carboxyphenyl)retinamide = 4-C6H4-COOH, N-(4-carboxyphenyl)retinamide
8. 5,6-all-trans-Epoxyretinoids
R = C O O H , 5,6-epoxyretinoic acid = C O O C H 3 , 5,6-epoxyretinoic acid methyl ester = C H 2 O C O C H 3 , 5,6-epoxyretinyl acetate . 13-cis-Retinoic acid derivatives
[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
R =
= = = = =
47
OH, 13-cis-retinoic acid NHC:Hs, N-ethyl-13-cis-retinamide NH(2-C2H4OH), N-(2-hydroxyethyl)-13-cis-retinamide NH(4-C6H4OH), N-(4-hydroxyphenyl)-13-cis-retinamide leucine, N-(13-cis-retinoyl)leucine phenylalanine, N-(13-cis-retinoyl)phenylalanine
10. Bifunctional retinoic acid analogs
RI, R2 = COOH, COOH, 14-carboxyretinoic acid ----- C O O C 2 H 5 , COOC2H5, ethyl 14-(ethoxycarbonyl)retinoate = CONHC2Hs, COOH, 14-[(ethylamino)carbonyl]-13-cisretinoic acid I 1.
Ring-modified all-trans-retinoic acid analogs
R~
O
O
H
R = [.~
a-retinoic acid
R = [~ IJ
= ~
,4-hydroxyretinoic acid
= [~ I~
C; ----CHsO ~
= ~]~,
phenyl analog of retinoic acid 4-methoxy' 2,3,6-trimethylphenyl analog of retinoic acid 5,6-dihydroretinoic acid
= [,. ]k. , 4-oxoretinoic acid
,3-pyridyl analog of retinoic acid , dimethylacetyl0ell5 cyclopentenyl analog of retinoic acid 2-furyi analog of retinoic acid
= ~
,3-thienyl analog of retinoic acid
48
STRUCTURE
AND
ANALYSIS
[3]
12. Side-chain-modified all-trans-retinoic acid analogs
R
=
.~OOH
, C~5 analog of retinoic acid
=
,,(~,..~'~C 00H
, C17
~ O O H ~~~C00H
, C22 analog of retinoic acid
= =
analog of retinoic acid
, aryltriene analog of retinoic acid
~/~~.~C
0OH
,7,8-dihydroretinoic acid
=
~~~./,C
00H
,9,10-dihydroretinoic acid
=
~ ~ ~ , C
00H
, I l, 12-dihydroretinoic acid
13. Ring- and side-chain-modified analogs of all-trans-retinoic acid
~
OOH
(E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyi-2-naphthalenyl)-lpropenyl]benzoic acid
~
OOH
(E)-4-[2-(5,6,7,8-Tetrahydro-8,8-dimethyl-2-naphthalenyl)-l-propenyl]benzoic acid
~
OOH
(E)-4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamolyl]benzoic acid
[3]
STRUCTURAL CHARACTERISTICS OF SYNTHETIC RETINOIDS
~
49
OOH
(E)-4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid
~
OOH
(E)-4-[2-(2,3-Dihydro- 1,1,2,3,3-pentamethyl- I H-inden-5-yl)- 1-propenyl]benzoic acid
~
OOH
6-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid
~
~COOH
6-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-5-methyl2-naphthalenecarboxylic acid
2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-6-benzo[b] thiophenecarboxylic acid
50
STRUCTURE
~
[4]
AND ANALYSIS
.COOH
4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid
~
COOH
(E)-4-[3-(3,5-Di-tert-butylphenyl)-3-oxo-l-propenyl]benzoicacid
[4] H i g h - P e r f o r m a n c e Liquid C h r o m a t o g r a p h y o f R e t i n o i d s in Blood
By A. P. DE LEENHEER and H. J. NELIS Introduction
The principal form of vitamin A in blood under fasting conditions is retinol. ~This compound is mobilized from retinyl ester stores in the liver and circulates in association with its specific transport protein [retinolEG. A. J. Pitt, in "Fat-Soluble Vitamins--Their Biochemistry and Applications" (A. T. Diplock, ed.), p. 1. Heinemann, London, 1985.
METHODS IN ENZYMOLOGY, VOL. 189
Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
