IMIDAZOLE NUCLEOSIDES AND NUCLEOTIDES LEROY B. TOWNSEND
Department of Chemistry, University of Utah, Salt Lake City, Utah 84118 Received January 85, 1961 CONTENTS
I. Introduction, Scope, and Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Chemical Synthesis of Imidazole Nucleosides and Nucleotides, .........................
111. IV.
V.
VI. VII.
533 534 A. Condensations of Heavy Metal Salts of Preformed Imidazoles with Acylglycosyl Halides 534 B. Ring Closure of Glycosylamines.. .............................................. 538 C. Degradation or Ring Opening of Purine Nucleosides and Nucleotides.. . . . . . . . . . . . . . . 541 546 D. Acid-Catalyzed Fusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Miscellaneous. . ..................... 547 Imidazole Nucleosid ucleotide Biosynthesis, . . . . . . 547 Other Naturally Occurring Imidazole Nucleosides and Nucleotides. ........ 550 A. Histidine Biosynthesis. ........................................................ 550 B. Substituted Imidazole-Adenine Dinucleoside Pyrophosphates (Coenzyme Analogs). . . 551 C. Histamine Biosynthesis and Metabolism.. ....................................... 552 552 D. Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Miscellaneous.. . . ............................ . . . . . . . . . 553 554 2’-Deoxyribofuran es . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554 Tables ........... .............................. 561 References.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION, SCOPE,AND NOMENCLATURE This review covers the area of synthetic and naturally occurring imidazole nucleosides, nucleotides, and various related derivatives. Certain biochemical aspects of these compounds are also reviewed briefly. This ring system has been designated as glyoxaline, iminazole, l,&diazole, and imidazole. The first preparation of the parent ring system was accomplished (57) from ammonia and glyoxal; hence the origin of the term glyoxaline is self-evident and is still used extensively in some areas. The terms iminazole and 1,3-diazole are very rarely used in the recent literature. Imidazole, which is the term (83) applied most frequently to this ring system, indicates a five-membered heterocyclic ring system containing an imino group and a tertiary nitrogen and will be used throughout this review. It was originally proposed (108) that the term nucleoside be used only for carbohydrate derivatives of purines and pyrimidines isolated from the alkaline hydrolyzates of yeast nucleic acid. This was found t o limit the use of this term since the major carbohydrate constituents of yeast nucleic acid are either Dribose or 2-deoxy-~-erythro-pentose (2-deoxy-~-ribose). It has now been generally accepted that the term purine nucleoside refers to all glycosyl derivatives of purines, both synthetic and natural, and it seems logical at this time to extend this concept of terminology to encompass the entire field of nitrogen heterocycles. Therefore, in this review all glycosyl derivatives (133) of imidazoles, regardless of the nature of the carbohy533
drate moiety, will be referred to as imidazole nucleosides. The term imidazole nucleotide will be used when a phosphate ester has been formed on a hydroxy group of the carbohydrate moiety of an imida~ole nucleoside. The numbering system will use numerals to designate positions on the aglycon and primed numerals for positions on the carbohydrate moiety. Numbering of the aglycon always begins at the substituted nitrogen and proceeds so that the second nitrogen in the ring is at position 3. Numbering of the carbohydrate moiety originates a t the anomeric carbon which is the carbon involved in the glycosidic linkage.
A number of reviews have (26, 47, 79, 85, 125, 149) presented some imidazole nucleoside and nucleotide chemistry or biochemistry but only in connection with another subject. It is the object of this review to summarize and complement these previous reports and present a complete and comprehensive review on imidazole nucleosides and nucleotides. The generally accepted nomenclature (68, 133) has been used in this review. The literature survey pertaining to this re-
LEROYB. TOWNSEND
534
view was essentially concluded in June 1966 although a few more recent references have been included.
11. CHEMICAL SYNTHESIS OF IMIDAZOLE NUCLEOSIDES AND NUCLEOTIDES The chemical preparation of imidazole nucleosides is a relatively new area in comparison to the related areas of purine and pyrimidine nucleosides. The discovery that nucleic acids contained purine and pyrimidine nucleotides generated an early interest in the chemical synthesis of analogs of these naturally occurring compounds. Interest in the area of imidazole nucleosides and nucleotides developed rather slowly but has recently escalated rapidly. The major factor involved in this increased interest can probably be attributed to the fact that the major purine nucleotides found in nucleic acids depend on imidazole nucleotides as precursors. A.
CONDENSATIONS OF HEAVY METAL SALTS OF
PREFORMED IMIDAZOLES WITH ACYLGLYCOSYL HALIDES
The first reported chemical synthesis of an imidazole nucleoside was accomplished in connection with the elucidation of the site of glycosidic attachment of purine nucleosides isolated from nucleic acid. The condensation of a-acetobromoglucose (I) with the silver salt of 5(4)-methylimidazole (11) in a non+
polar solvent produced (80) the first crystalline synthetic imidazole nucleoside, 5-methyl-1-(2’,3’,4’,6’tetra-0-acetyl-fi-D-glLl Co p y r an0 s yl)imi d azo1e (111). Elucidation of the site of glycosidation was accomplished by alkylation of I11 with methyl iodide to afford a methiodide derivative of IV. Conversion of IV to the methochloroaurate derivative (V) followed by acid hydrolysis resulted in the isolation of 1,4-dimethylimidazole chloroaurate (VI). The structure of VI was established by a comparison of its solubility and melting point with the previously prepared (143) 1,4- and 1,5-dimethylimidazole chloroaurates and corroborated the initially assigned site of glycosidation. The stability of imidazole nucleosides was firmly established when V was recovered unchanged after refluxing in 21% hydrochloric acid for 1.5 hr; 38% hydrochloric acid at 150” for 2 hr was finally required to cleave the glycosidic bond. Although I11 was the only crystalline nucleoside isolated, it was suggested that the isomeric compound, 4-methyI-1-(2’,3’,4’,6’-tetra-O-acetylfi-D-ghcopyranosyl)imidazole (VII), was present in the mother liquor of the original reaction mixture. This type of condensation with subsequent deacetylaCH3300
171-172
Recryst solvent
deg (solvent)c
Triturated with ethanol
+78 (d)
Spectra
32
I11
161
Paper chromatogmphy
VI
36
Paperchromatography
I11
36
v Paperchromatography Bariumsalt
V
120 92
VI
170
I1
165
I11
162
Ethanol-water
UV
uv
K B
Water-acetone As above
-26.3 (0)
P p t d out of water with ethanol
I 186-187 dec
UV UV
Water
Hoco 207-209
HO
Ref
VI
UV IR
As above
HOOCCH,-P+JNJ HOOCdHz HzN
Mixd
Method of prepd
Aqueoua (pH 5)
OH
UV
Paperchromatography
I11
183
UV
Paperchromatography Paperchromatography Paperchromatography
I11
183
I11
183
I11
183
VI
162
As above
2'-Phosphate 3'-Phosphate
UV UV
6'-Phosphate 186-187
Ethanol-water
As above 0
II
0
Water, pptd with ethanol Water, pptd with ethanol
HO- P- 0-CH, bH
HO
OH
172 dec
Bariumsalt
VI
168
UV
Barium salt
v
121
VI
154
I1
165
I11
134
IR PMR
58-60
Ho@P-
UV
Picrate
Water
OH
Homo HO
OH
113
Ethanol
UV
Paperchromatography
558
LEROYB. TOWNSEND TABLE I1 (Continued) [ab,
Imidazole m o i e t 9
G~YCOB moiety* Y~
MP, OC
Recryet solvent
der (solvent)c
Spectra
Mhod
Method of prepe
Ref
0
HO 0
As above
As above
*O
sintering Ethanol-water 175-180, and melting 216
-40 (e)
I
39
Sintering at Ethanol-water 175-180, melting a t 215-216 dec
+44 (e)
I
39
132-133
Ethanol, thenEtzO and petr ether (40-60°)
VI
39
232-233 146-148
Ethanol-pyridine Aqueous ethanol 88 monohydrate
VI
VI
39 39
VI
39
I
37
VI
37
I
91
OAc Ac
As above
AcOCHz As above A OAc HOCH, As above
208-210 dec
Methanol-water
As above
184-185
EthanOl-Water
As above
218-220 (rapid heating)
Water
215-216
Ethanol-water
+17
(8)
VI
37
246-248
Ethanol
+55 (f)
VI
37
$34 (a)
VI
39
VI
39
VI
80
VI
80
VI
154
IV
154
-4 (a)
Ad)CH1
HO
OH
As above
HO HO HO As above
&?-
A
AcO
OAc
As above HO
A s above
&+-
* &*
Ad)
Sintering a t Ethanol-water 165-170 and melb ing at 224-225 dec 158-189 Ethanol
OAc
FH3 AuCI,
144-145
HO
AcO
232 dec
Ethanol
OAc 180-182
A"co HO
As above
OH
93-95
AcO
OAc
IMIDAZOLE NUCLEOSIDES AND NUCLEOTIDES
559
TABLEI1 (Continued) bh RWWlt
Imidazole moietfl
Glycowl moiety*
MP, O C
204 O\
solvent
deg (solvent)c
Method of Spectra
Mhcd
Ethanol
prep'
Ref
111
132
V
177
V
177
I11
32
P
CH3 CH,
Hd
dH
w
6%
243-244 dec
uv
Methanol
IR
F
0
Hoco HO
As above
175-177
Methanol
148-150
Ethanol
Adco AcO
UV
Paperchromatography
I
28
UV
Paperchromatography
I
28
VI
95
VI
164
HC1 salt
I
34
Paperchromatography
I
35
I1
168
I
80
VI
168
VI
171
I1
51
OH
99-100
OAc
-0.6 (a)
uv +11.2 (f)
IR
CCL and petr ether
As above
206-207
AdCH2
176
+ & J
A
'
OAc
HO
OH
Ethanol
Diethyl ether and water
Hoco 152
Residue triturated with ethyl acetate
0
uv Pptd out of water with ethanol Hb
OH
Bariumsaltand paper chromatography
560
LEROYB. TOWNSEND TABLE I1 (Continued) Glycosyl moietyb HOCH, 0
0
As above
MP, 'C
161-162
ID,
Method of prepd
Ref
Ethyl acetate
VI
168
Methanol
I1
168
VI VI VI
60 60 60
I
39
I
39
I
96
VI
95
I
85
la
I r 5 h z o l e lnoietjP
Recryst solvent
deg (solvent)'
Spectra
Misod
O Y CHa C&
ca8m 0
223-225
AS above
dec
O
.d
F
o
207-209 198-200 130, solid-
Methanol Methanol Dilute ethanol
Neut equiv Neut equiv Dipicrate
ify then melting a t 174AcOCHz
As above
176 123
Methanol
168-167
Methanol
116-118
Methanol
Glass
f 2 2 . 6 (f)
uv
UV
I
Pape;chromatography
As above 164-165
Methanol
Hoco As above
A8 above
+i?
255-256
Methanol
uv
VI
28
115-118
Ethanol
uv
I
28
185-187
Methanol
uv
VI
28
149-150
Methanol
I
28
HO As above
0 The position of glycosidic attachment to the imidazole moiety can be easily determined by vkual inspection, and all compounds are of the p configuration unless they possess a wavy line a t the anomeric center which denotes either an anomeric mixture or a compound of unknown or undetermined anomeric configuration. * The abbreviation -OAc denotes -OCOCHa. c Solvents used in the determinstion of optical rotations appear as letters in parentheses: (a) water, (b) methanol, (c) 0.1 M sodium bicarbonate, (d) 4: 1 water-pyridine, (e) pyridine, ( f ) chloroform, ( g ) ethanol, (h) 80% ethanol, (i)24% sulfuric acid. d I R = infrared; W = ultraviolet; PMR = proton magnetic resonance. e Key to the method of preparation: I, condensation of heavy metal salt of preformed imidazole with acylglycosyl halide; 11, ring closure of glycosylamine; 111, degradation or ring opening of purine nucleoside or nucleotide; IV, acid-catalyzed fusion; V, naturally occurring or enzymatic synthesis; VI, transformation of a preformed imidazole nucleoside or nucleotide.
IMIDAZOLE NUCLEOSIDES AND XUCLEOTIDES ACKNOWLEDGMENTS.--The author wishes to express his sincere appreciation to Professor Roland K. Robins for encouragement, for a critical reading of the manuscript, and for many valuable suggestions. The author is grateful to Dr. Ralph L. Shriner for the opportunity to prepare this manuscript and appreciates the cooperation of a number of colleagues, especially R. J. Rousseau and A. F. Lewis. He also expresses his gratitude for the continuous encouragement and assistance of his wife, Sammy, and to Miss Dorlene Kearl for preparation of the manuscript. The author is indebted to the Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health, Public Health Service, for financial support on Research Contract P H 43-65-1041. VII. REFERENCES (1) Abdel-Latif, A. A,, and Alivisatos, S. G. A., J . Biol. Chem., 236, 2710 (1961). (2) Abdel-Latif, A. A., and Alivisatos, S. G. A., Biochim. Bwphys. Acta, 51,398 (1961). (3) Aebi, A., Helv. Chim. Acta, 39, 1495 (1956). (4) Ahmad, F., Missimer, P., and Moat, A. G., Can. J . Biochem., 43, 1723 (1965). (5) A jinomoto Co. Inc., Japanese Patent 3550 (1962); Chem. Abstr., 58, 5012f (1963). (6) Ajinomoto Co. Inc., French Patent 1,375,784 (Oct 23, 1964); Chem. Abstr., 63, 18999g (1965). (7) Ajinomoto Co. Inc., Dutch Patent 6,409,142 (Feb 17, 1965); Chem. Abstr., 63, 57313 (1965); Dutch Patent 6,409,133 (Feb 8, 1965); Chem. Abstr., 63, 3029a (1965); Dutch Patent 6,409,806 (March 1, 1956); Chem. Abstr., 63, 10055c (1965). (8) Ajinomoto Co. Inc., Japanese Patent 1534 (Feb 4, 1966); Chem. Abstr., 64, 12781e (1966). (9) Alivisatos, S. G. A., Federation Proc., 17, 180 (1958). (10) Alivisatos, S. G. A., Nature, 181, 271 (1958). (11) Alivisatos, S. G. A., Nature, 183, 1034 (1959). (12) Alivisatos, S. G. A., Federation Proc., 24, 769 (1965). (13) Alivisatos, S. G. A,, Abdel-Latif, A. A., Ungar, F., and Mourkides, G. A., Nature, 199, 907 (1963). (14) Alivisatos, S. G. A., and LaMantia, L., Biochem. Biophys. Res. Commun., 2, 164 (1960). (15) Alivisatos, S. G. A,, LaMantia, L., and Matijevitch, B. L., Biochim. Biophys. Acta, 58, 201 (1962). (16) Alivisatos, S. G. A., LaMantia, L., Ungar, F., and Matijevitch, B. L., J. Biol. Chem., 237, 1212 (1962). (17) Alivisatos, S. G. A,, LaMantia, L., Ungar, F., and Savich, B., Biochim. Biophys. Acta, 30, 660 (1958). (18) Alivisatos, S. G. A,, Ungar, F., Lukacs, L., and LaMantia, L., J . Biol. Chem., 235, 1742 (1960). (19) Alivisatos, S. G. A., Ungar, F., and Mourkides, G. A., Nature, 211, 187 (1966). (20) Alivisatos, S. G. A., and Woolley, D. W., J . Am. Chem. SOC.,77, 1065 (1955). (21) Alivisatos, S. G. A., and Woolley, D. W., J. Biol. Chem., 221, 651 (1956). (22) Allesbrook, W. E., Gulland, J. &I., and Story, L. F., J . Chem. SOC.,232 (1942). (23) Ames, B. N., Martin, R. G., and Garry, B. J., J . Biol. Chem., 236, 2019 (1961). (24) Ames, B. N., and Mitchell, H. K., J . Am. Chem. SOC., 74, 252 (1952).
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