Research Article
Austin J Anal Pharm Chem. 2017; 4(3): 1090.
Development of a New Spectral Tool for Identification of E and Z Isomers of Retinoids
Mohanraj SM1* and McMurry JE2
1PolyMicrospheres, Division of Vasmo Inc., Indianapolis, IN, USA
2Baker Laboratory, Department of Chemistry, Cornell University, Ithaca, NY, USA
*Corresponding author: Mohanraj SM [1], PolyMicrospheres, Division of Vasmo Inc., 4101 East 30th Street, Indianapolis, IN 46218, USA
Received: September 01, 2017; Accepted: September 27, 2017; Published: October 04, 2017
Abstract
A spectral study of a new series of fifteen retinoids based on the dimethyltetralin ring system, leading to the development of a new “Spectral Tool” for identification of E and Z isomers, is reported. Four types of retinoids (A-D), promising therapeutic agents for the treatment of epithelial cancer, were reported recently, in which various side-chain double bonds are rigidly held in specific conformations. Among the most active retinoids, the 9E isomers are 40-60 times more active than the corresponding 9Z isomers. In this study, a complete assignment of the 1H and 13C NMR signals of the retinoids to specific hydrogen and carbon atoms was achieved on the basis of chemical shifts, multiplicity, coupling constants, and assessment of substituent effects (i.e. shift changes upon alteration of the chemical structure), and comparisons of chemical shifts from compound to compound and of related compounds, and by proton noise-decoupled spectra and single frequency off-resonance decoupled spectra. The chemical shift differences between the 9E and the corresponding 9Z isomers are discussed, and interesting chemical shift patterns are observed. The distinct chemical shift patterns of the 9E and the 9Z retinoids in the 1H and 13C NMR could be used as a spectral tool to identify the E and Z isomers of other retinoids and vitamin A analogs.
Keywords: cis-and trans-retinoids; 1H and 13C NMR of E and Z isomers of retinoids
Introduction
The retinoids, a large class of polyunsaturated diterpenes structurally related to vitamin A, have aroused much interest because of their diverse biological properties [2] and versatile isomeric structures. In particular, the effect of vitamin A on epithelial tissues [2] has attracted much attention because vitamin A deficiency leads to hyperkeratosis of the skin and to metaplastic changes in the epithelia of gastrointestinal, respiratory, and urogenital tracts.
A number of synthetic retinoids have proven to be extremely effective in the treatment of various types of keratinization disorders [2]. Although a large number of retinoids have been synthesized, only limited work has been done on the NMR spectral study of retinoids and vitamin A derivatives [3,4].
The retinoic acid molecule is composed of three building units – a nonpolar cyclic end group, a polyene chain and a polar head group. Although it is relatively easy to probe structure-activity relationships involving the cyclic end group and polar head group, side-chain effects on biological activity are more difficult to study. The conformational flexibility of the side chain makes it possible for retinoids to adopt a large number of conformations, some of which are biologically active while others are inactive.
We recently reported [5] the development of four types of new retinoids containing dimethyltetralin end groups (A-D in Chart 1), in which various side-chain double bonds are rigidly held in specific conformations. Bicyclic type A analogs have the 5,6 and 7,8 double bonds of the retinoic acid locked into an s-cis conformation without disturbing the rest of the molecule, while tricyclic analogs of types B–D have additional constraints on double bond geometry imposed by introduction of a third ring.
Chart 1: Structures of new Retinoids.
(Type A: 10-11, Type B: 15-16, Type C: 18-19, and Type D: 21-22)
In all of the fifteen new synthetic retinoids reported [5], three of which (18a, 18b, and 10b) exhibited ED50(M) values in the (3-5) x10-11 range, and are promising candidates for the prevention and treatment of epithelial cancer. In this series of retinoids, the 9-trans retinoids (E isomers) are more active than their 9-cis retinoids (Z isomers). Comparing the ED50(M) values of the most active retinoids, the 9E isomers are 40-60 times more active than the corresponding 9Z isomers.
In this paper, we report the high resolution 1H and 13C NMR spectral study of these four types of retinoids leading to the development of a new “Spectral Tool” for identification of E and Z Isomers. We were able to use the interesting chemical shift patterns of the 9E and the 9Z retinoids in the 1H NMR as a tool to pinpoint the 9E and 9Z isomers. The distinct chemical shift patterns of the 9E and the 9Z retinoids in the 13C NMR were used as a better tool to distinguish between 9E and 9Z isomers.
Numbering the skeletal atoms of retinoids
Numbering the skeletal atoms of retinoids is based on standard retinoid numbering. Carbon numbering of the retinoids closely resembles that for retinoic acid. The numbering the new synthetic retinoids were done with assistance from the editor of Nomenclature, Chemical Abstract Service [6].
Experimental
1H NMR spectra were run at 300 MHz on a Bruker WM 300 spectrophotometer in CDCl3 with Me4Si as internal standard. 13C NMR spectra were run at 22.49 MHz on a JEOL FX 90Q spectrometer at 25 °C in CDCl3 with Me4Si as internal standard. Chemical shifts were reported in ppm relative to Me4Si (d=0).
Spectral Study leading to the development of a new “Spectral Tool” for identification of E and Z isomers
1H NMR Studies: Tables 1-3 list the chemical shifts (d, ppm), multiplicity, and coupling constants (J, Hz) of synthetic retinoids 10a- 22. A complete assignment of the 1H NMR signals of the retinoids to specific hydrogen atoms in Tables 1-3 was achieved on the basis of chemical shifts, multiplicity, coupling constants, and assessment of substituent effects (i.e. shift changes upon alteration of the chemical structure), and comparisons of chemical shifts from compound to compound and of related compounds. 1H NMR data and their assignment to specific hydrogen atoms for retinoids 10a, 10b and 11 are reported in Table 1, for retinoids 15, 16, 21 and 22 in Table 2, and for retinoids 18a-19d in Table 3. Significant chemical shifts differences between the 9E and the 9Z isomers of retinoids [absolute value of (d9E – d9 Z) > 0.05ppm] are summarized in Table 4.
Retinoid No.®
H¯. ¯
10a (9E)
(R = CH3)
11(9Z)
(R = CH3)
10b (9E)
(R = H)
H-2
1.67 (dt, 2, 5.8)
1.68 (dt, 2.2, 5.7)
1.67 (dt, 2, 5.8)
H-3
1.80 (m)
1.81 (m)
1.80 (m)
H-4
2.77 (t, 6.2)
2.78 (t, 6.0)
2.77 (t, 6.2)
H-7
7.42 (d, 1.8)
7.20 (d, 1.6)
7.43 (d, 1.7)
H-10
6.54 (d br, 11.1)
6.23 (d, 11.0)
6.56 (d br, 11.2)
H-11
7.04 (dd, 11.3, 15.1)
6.80 (dd, 11.1, 15.2)
7.08 (dd, 11.1, 14.9)
H-12
6.38 (d, 15.2)
6.26 (d, 15.1)
6.41 (d, 15.1)
H-14
5.81 (s br)
5.75 (s br)
5.84 (s br)
H-16 & 17
1.31 (s)
1.29 (s)
1.32 (s)
H-18
7.03 (d, 8.1)
7.06 (d, 8.1)
7.04 (d, 8.0)
H-19
2.25 (d, 0.8)
2.18 (s)
2.26 (s)
H-20
2.39 (d, 0.8)
2.18 (s)
2.40 (s)
H-21
7.19 (dd, 1.9, 8.0)
6.98 (dd, 1.7, 7.9)
7.20 (dd, 1.8, 7.9)
H-Functional Group
3.72 (s, -COOCH3)
3.69 (s, -COOCH3)
-
Table 1: 1H NMR Spectral Shifts of Retinoids 10a, 10b and 11.
Retinoid No. ®
H¯. ¯
15
(9E)
16
(9Z)
21
(9E)
22
(9Z)
H-2
1.67 (m)
1.69 (m)
1.66 (m)
1.61 (m)
H-3
1.79 (m)
1.82 (m)
1.79 (m)
1.77 (m)
H-4
2.76 (t, 6.3)
2.79 (t, 6.3)
2.75 (t, 6.3)
2.74 (t, 6.3)
H-7
7.44 (d, 1.8)
7.25 (d, 1.8)
7.44 (d, 1.8)
7.11 (s br)
H-10
6.58a (d br, 11)
6.27 (d, 11)
6.52 (s br)
6.21 (s br)
H-11
7.17b (m)
6.99b (m)
-
-
H-12
6.58a (d br, 15)
6.45 (d, 15.4)
6.75 (s br)
6.41 (s br)
H-14
6.93 (d, 2.2)
6.75 ( d br, 2.2)
6.65 (s br)
6.34 (s br)
H-16 & 17
1.32 (s)
1.31 (s)
1.31 (s)
1.10 (s)
H-18
7.01a (d, 8.1)
6.99b (m)
7.01 (d, 7.7)
6.99 (d, 8)
H-19
2.25 (s)
2.18 (s)
2.24 (d, 1.1)
2.17 (d, 1.5)
H-20
7.01a (d, 8.1)
6.99b (m)
2.29 (s)
2.13 (s)
H-21
7.17b (m)
6.99b (m)
7.19 (dd, 1.8, 7.7)
6.94 (dd, 1.8, 8)
H-22
7.17b (m)
6.99b (m)
6.68 (s br)
6.37 (s br)
H-23
6.68 (dd, 1.8, 7.4)
6.62 (dd, 2.2, 8.1)
-
-
-OH
5.08 (br)
4.7 (br)
5.24 (br)
4.33 (br)
Table 2: 1H NMR Spectral Shifts of Retinoids 15, 16, 21 and 22.
Retinoid No. ®
18a (9E)
19a (9Z)
18b(9E)
19b(9Z)
18c(9E)
19c(9Z)
18d(9E)
19d(9Z)
H¯. ¯
(R=COOMe)
(R=COOH)
(R=CH2OH)
(R=CHO)
H-2 (m or dt, 2,6)
1.68
1.60
1.69
1.60
1.68
1.61
1.68
1.61
H-3 (m)
1.81
1.77
1.82
1.78
1.81
1.77
1.81
1.78
H-4 (t, 6.3)
2.78
2.73
2.78
2.75
2.78
2.73
2.78
2.74
H-7 (d, 1.8)
7.47
6.98a(m)
7.47
6.99a(m)
7.46
7.08a(m)
7.47
7.05
H-10 (s br)
6.79
6.45
6.81
6.48
6.77
6.43
6.80
6.47
H-12&22 (d, 8)
7.43
6.98a(m)
7.46
6.99a(m)
7.37(s br)
6.96(m)
7.51
7.11
H-13&23(d,8)
8.03
7.77
8.12
7.83
7.37(s br)
6.96(m)
7.87
7.61
H-16&17 (s)
1.33
1.08
1.34
1.08
1.33
1.09
1.33
1.06
H-18 (d, 8)
7.06
6.98a(m)
7.06
6.99a(m)
7.05
7.08a(m)
7.06
7.00
H-19 (d, 1.1)
2.29
2.21
2.30
2.23
2.27
2.19
2.31
2.23
H-21(dd, 2,8)
7.23
6.98a(m)
7.24
6.99a(m)
7.24
7.08a(m)
7.23
6.92
H-Functional Group (R=)
3.92 (s)
(COOCH3)
3.83 (s)
(COOCH3)
-
-
4.71 (s)
(CH2OH)
4.54 (s)
(CH2OH)
9.81 (s)
(CHO)
9.87 (s)
(CHO)
anot resolved, merged with other signals.
Table 3: 1H NMR Spectral Shifts of Retinoids 18a-d and 19a-d.
Retinoid No. ®
H¯. ¯
10a - 11
R=Me
15-16
21-22
18a - 19a
R=COOMe
18b - 19b
R=COOH
18c - 19c
R=CH2OH
18d - 19d
R=CHO
H-2
-
-
-
0.08
0.09
0.07
0.07
H-7
0.22
0.19
0.33
0.49
0.48
0.38
0.42
H-10
0.31
0.31
0.31
0.34
0.33
0.34
0.33
H-11
0.24
0.18
-
-
-
-
-
H-12
0.12
0.13
0.34
0.45
0.47
0.41
0.40
H-13
-
-
-
0.26
0.29
0.41
0.26
H-14
0.06
0.18
0.31
-
-
-
-
H-16 & 17
-
-
0.21
0.25
0.26
0.24
0.27
H-18
-
-
-
0.08
0.07
-
0.06
H-19
0.07
0.07
0.07
0.08
0.07
0.08
0.08
H-20
0.21
-
0.16
-
-
-
-
H-21
0.21
0.18
0.25
0.25
0.25
0.16
0.31
H-22
-
0.18
0.31
0.45
0.47
0.41
0.40
H-23
-
0.06
-
0.26
0.29
0.41
0.26
H-Functional Group (R=)
-
-
-
0.09
(COOMe)
-
0.17
(CH2OH)
0.06
(CHO)
Table 4: Significant Chemical Shift Differences d9E – d9Z (abs. value > 0.05 ppm) in the 1H NMR Signals of Retinoids.
The 11E double-bond configuration for retinoids 10a, 10b, and 11 was established from the 15 Hz coupling constants for H-11 and H-12. The all-E configuration for 10a and 10b was established by comparison of their 1H and 13C NMR spectra with those of known retinoids [3,4]. In the known retinoids, a strong downfield shift (~1.4ppm) of H-12 and a significant upfield shift (~0.3ppm) of H-20 relative to those of all-E retinoids are characteristic of 13Z configuration. Although H-20 of retinoid 11 is shifted upfield (0.21ppm) relative to that of 10a, the absence of a downfield shift of H-12 (shifted upfield 0.12ppm) relative to that of 10a favors a13E geometry for 11. The 13E configuration is also supported by the 13C NMR spectra (discussed infra). A significant upfield shift (0.31ppm) of H-10 in 11 relative to that of 10a favors a 9Z geometry for 11, which was established from the 13C NMR spectra (discussed infra).
The 15 Hz coupling constant for H-12 in retinoids 15 and 16 is indicative of an 11E configuration. An upfield shift of H-10 (0.31-0.34ppm) in retinoids 16, 22, and 19a-19d, relative to that of the corresponding all-E isomers favors a 9Z geometry. The 9Z configuration was further established by the 13C NMR spectra discussed later.
A study of the chemical shift differences between the 9E and the 9Z isomers of retinoids reported in Table 4 reveals interesting chemical shift patterns that make it possible to achieve the development of a new “spectral tool” to distinguish between 9E and 9Z isomers:
i) Most of the protons of 9Z retinoids exhibit an upfield shift relative to those of the corresponding 9E isomers. An overall greater steric interaction between hydrogen atoms occurs in the case of 9E retinoids leading to downfield shifts. Conversely, an overall reduction of specific steric compressions in the 9Z retinoids leads to corresponding upfield shifts in the 1H NMR spectra.
ii) A pronounced upfield shift of H-7 [Dd (9E-9Z): 0.2- 0.5ppm] occurs in all 9Z isomers of new retinoids.
iii) All 9Z retinoids exhibit an upfield shift (0.3ppm) of H-10.
iv) A significant upfield shift (0.2-0.3ppm) of H-21 is displayed in all 9Z retinoids.
v) A slight upfield shift (0.07ppm) of H-19 is experienced by all 9Z retinoids.
vi) An upfield shift [Dd (9E-9Z): 0.2-0.3ppm] of H-16 and H-17 is observed in tricyclic retinoids 18a-19d, 21, and 22.
vii) H-12 and H-22 show a pronounced upfield shift [Dd (9E- 9Z): 0.3-0.5ppm] in tricyclic retinoids 18a-19d, 21, and 22.
viii) H-13 and H-23 also show a pronounced upfield shift [Dd (9E-9Z): 0.3-0.4ppm] in tricyclic retinoids 18a-19d.
13C NMR Studies: Tables 5-7 list the chemical shifts (d, ppm) of synthetic retinoids 10a-11, 15-16, 18a-19d, and 21-22. A complete assignment of the 13C NMR signals of the retinoids to specific carbon atoms in Tables 5-7 was achieved on the basis of proton noisedecoupled spectra, single frequency off-resonance decoupled spectra, assessment of substituent effects, and comparisons of chemical shifts from compound to compound and of related compounds. 13C NMR data and their assignment to specific carbon atoms for retinoids 10a- 11 are reported in Table 5, for retinoids 15-16 and 21-22 in Table 6, and for retinoids 18a-19d in Table 7. Significant chemical shift differences between the 9E and the 9Z isomers of retinoids, a value of (d9E – d9Z) > 0.5ppm, are summarized in Table 8.
Retinoid No. ®
Carbon No. ¯
10a (9E)
(R=CH3)
11 (9Z)
(R=CH3)
10b (9E)
(R=H)
C-1
(s)
33.95
33.85
34.00
C-2
(t)
39.31
39.22
39.31
C-3
(t)
19.61
19.61
19.66
C-4
(t)
30.49
30.54
30.54
C-5
(s)
140.68
143.55
141.36
C-6
(s)
145.70
145.41
145.80
C-7
(d)
122.83
126.59
122.88
C-8
(s)
140.09a
138.19a
140.04a
C-9
(s)
136.04a
135.70a
136.24a
C-10
(d)
129.07
128.98
129.12
C-11
(d)
131.36
132.97
132.14
C-12
(d)
135.41
134.19
135.26
C-13
(s)
152.96
153.30
155.30
C-14
(d)
118.15
117.71
117.71
C-15
(s)
167.49
167.54
172.13
C-16 & 17
(q)
31.85
31.80
31.90
C-18
(d)
125.76
127.12
125.76
C-19
(q)
16.44
25.51
16.54
C-20
(q)
13.86
13.77
14.11
C-21
(d)
123.90
124.73
124.00
-COOCH3
(q)
50.92
50.87
-
Table 5: 13C NMR Chemical Shifts of Retinoids 10a, 10b, and 11.
Retinoid No. ®
Carbon No. ¯
15
(9E)
16
(9Z)
21
(9E)
22
(9Z)
C-1
(s)
33.90
33.90
33.95
33.70
C-2
(t)
39.31
39.36
39.36
39.31
C-3
(t)
19.61
19.76
19.66
19.76
C-4
(t)
30.44
30.58
30.44
30.54
C-5
(s)
140.43
140.48
141.51
141.80
C-6
(s)
145.55
145.50
145.60
145.50
C-7
(d)
122.69
127.61
123.03
125.76
C-8
(s)
137.56
138.78
138.00
138.97
C-9
(s)
135.41
135.26
135.26
134.83
C-10
(d)
128.98a
128.88a
128.93
129.02
C-11
126.34a (d)
126.93a (d)
139.95 (s)
139.31 (s)
C-12
(d)
131.71
130.34
122.73
122.69
C-13
(s)
139.60
139.75
139.31
139.12
C-14
(d)
112.69
112.59
114.15
113.76
C-15
(s)
155.60
155.65
155.11
154.91
C-16 & 17
(q)
31.80
31.90
31.85
31.51
C-18
(d)
126.15
126.93
126.44
127.17
C-19
(q)
16.20
25.51
17.66
26.83
C-20
119.17 (d)
119.13 (d)
21.32 (q)
21.27 (q)
C-21
(d)
123.71
125.17
124.15
124.59
C-22
(d)
129.71
129.66
112.98
112.50
C-23
(d)
114.35
114.01
-
-
aassignments interchangeable with the value marked a in the same column.
Table 6: 13C NMR Chemical Shifts of Retinoids 15, 16, 21 and 22.
Retinoid No. ®
18a(9E)
19a(9Z)
18b(9E)
19b(9Z)
18c(9E)
19c(9Z)
18d(9E)
19d(9Z)
Carbon No. ¯
R=COOMe
R=COOH
R=CH2OH
R=CHO
C-1
(s)
34.00
33.61
34.05
33.75
34.00
33.66
34.00
33.75
C-2
(t)
39.31
39.12
39.36
39.22
39.41
39.22
39.31
39.17
C-3
(t)
19.61
19.61
19.66
19.66
19.71
19.66
19.66
19.66
C-4
(t)
30.39
30.44
30.54
30.54
30.49
30.49
30.49
30.54
C-5
(s)
141.16
141.75
141.12
142.38
141.51
139.12
140.87
142.97
C-6
(s)
145.75
145.70
145.80
145.89
145.65
145.55
145.80
145.89
C-7
(d)
123.08
125.27
123.12
125.27
123.08
125.66
123.08
125.22
C-8
(s)
139.90
138.43
140.43
138.43
138.82
138.87
140.87
138.34
C-9
(s)
135.80
135.17
135.95
135.41
135.36
134.78
136.04
135.56
C-10
(d)
129.02
129.17
128.83
129.32
128.98
128.98
129.12
129.41
C-11
(s)
143.26
142.82
144.24
143.89
138.00
138.34
144.92
144.72
C-12 & 22
(d)
129.02
128.68
129.17
128.88
126.83
126.54
129.61
129.41
C-13 & 23
(d)
129.41
129.07
130.15
129.80
129.32
128.98
129.61
129.41
C-14
(s)
127.76
127.17
125.76
126.39
138.00
137.46
134.24
133.95
C-15
167.01(s)
166.86(s)
171.73(s)
172.17(s)
65.15 (t)
65.05 (t)
191.68(d)
191.73(d)
C-16 & 17
(q)
31.85
31.51
31.90
31.56
31.90
31.56
31.90
31.56
C-18
(d)
125.90
126.83
125.90
126.98
126.44
126.98
125.76
126.98
C-19
(q)
17.76
26.88
17.86
26.98
17.61
26.83
17.91
27.02
C-21
(d)
124.20
124.50
124.29
124.54
124.15
124.68
124.25
124.54
-COOCH3
(q)
51.94
51.74
-
-
-
-
-
-
Table 7: 13C NMR Chemical Shifts of Retinoids 18a-d and 19a-d.
Retinoid No. ®
Carbon No. ¯
10a -11
(R=Me)
15-16
21-22
18a - 19a
R=COOMe
18b - 19b
R=COOH
18c - 19c
R=CH2OH
18d-19d
CHO
C-5
-2.9
-
-
-0.6
-1.3
2.4
-2.1
C-7
-3.8
-4.9
-2.7
-2.2
-2.2
-2.6
-2.1
C-8
1.9
-1.2
-1.0
1.5
2.0
-
2.5
C-9
-
-
-
0.6
-
0.6
-
C-11
-1.6
-0.6
0.6
-
-
-
-
C-12
1.2
1.4
-
-
-
-
-
C-14
-
-
-
0.6
-0.6
-
-
C-18
-1.4
-0.8
-0.7
-0.9
-1.1
-
-1.2
C-19
-9.1
-9.3
-9.2
-9.1
-9.1
-9.2
-9.1
C-21
-0.8
-1.5
-
-
-
-
-
Table 8: Significant Chemical Shift Differences d9E – d9Z (value > 0.5 ppm) in the 13C NMR Signals of Retinoids.
The all-E configuration for 10a and 10b was established by comparison of their 13C NMR spectra with those of known retinoids [4]. The C-12 and C-20 resonances occurring at 134-135 and 14ppm in retinoids 10a-11 supports a 13E configuration. The C-10 signal at 129ppm in retinoids 10a-11 and 15-16 is in agreement with 11E geometry. Changing the stereochemistry at the 9, 10-double bond from E to Z is expected to cause an upfield shift of C-8 and a downfield shift of C-19. A 9ppm downfield shift of C-19 is observed for all 9Z retinoids. An upfield shift [Dd (9E-9Z): 1.5-2.5ppm] of C-8 is also observed in the 9Z retinoids 11, 19a, 19b, and 19d.
A study of the chemical shift differences between the 9E and the 9Z isomers of retinoids reported in Table 8 reveals distinctive chemical shift patterns that make it possible to achieve the development of a new “spectral tool” to distinguish between 9E and 9Z isomers:
i) Most of the carbons of 9Z retinoids exhibit a downfield shift relative to those of the corresponding 9E isomers. An overall reduction of specific steric compressions occurs in the 9Z retinoids leading to downfield shifts in the 13C NMR spectra.
ii) All the 9Z retinoids exhibit a pronounced downfield shift [Dd (9E-9Z): -9ppm] of C-19.
iii) The C-7 resonance shows a downfield shift of 2-5ppm in all 9Z retinoids.
iv) A slight downfield shift (0.5-1.2ppm) of C-18 is displayed for all 9Z retinoids.
Conclusion
The complete assignment of the 1H and 13C13C NMR signals of the fifteen new retinoids to specific hydrogen and carbon atoms was achieved. We were able to use the distinctive chemical shift patterns of the 9E and the 9Z retinoids in the 1H and 13C NMR to achieve a new “spectral tool” to pinpoint the 9E and 9Z isomers. This spectral tool could be utilized to identify the E and Z isomers of other retinoids and vitamin A analogs.
Acknowledgement
This work was supported by the National Cancer Institute through contract No. 1-CP-05716.
References
- The work in this paper was performed by Mohanraj SM at Cornell University, Ithaca, NY.
- Alvarez R, Vaz B, Gronemeyer H, Lera AR. Functions, therapeutic applications, and synthesis of retinoids and carotenoids. Chem. Rev. 2014; 114: 1-125.
- Vetter W, Englert G, Rigassi N, Schwieter U. in Isler O, Gutmann H, SolmsV. eds. Carotenoids, Birkhauser Verlag, Basel. 1971; 213-225.
- Englert G. Helv. A 13C-NMR. Study of cis-trans Isomeric Vitamins A, Carotenoids and Related Compounds. Chim. Acta.1975; 58: 2367.
- Mohanraj SM and McMurry JE. Development of New Retinoids for Treatment of Epithelial Cancer. Austin J. Anal. Pharm. Chem. 2017; 4: 1089.
- We thank Merritt JE, Senior Associate Editor, Nomenclature, Chemical Abstract Service, Columbus, OH, for her assistance in numbering the new retinoids.
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