Various Methods for Synthesis of Purine Analogues
Sachan Dinesh*, Pandeya S.N. and Pathak A.K.
Department of Pharmaceutical Sciences, Saroj Institute of Technology and Management, Lucknow.
*Corresponding Author E-mail: sachan1771@gmail.com
ABSTRACT:
The purine analogues are new class of nonclassical antimicrobial agents that binds with riboswitches. Purine (adenine) analogues are having antimicrobial, antifungal, antitumour, antiproliferative, antiviral and activity against HSV-1. Riboswitches are structured RNA domains that can bind directly to specific ligands and regulate gene expression. These RNA elements are located most commonly within the non-coding regions of bacterial mRNAs, because these genes were involved in fundamental metabolic pathways in certain bacterial pathogens. Purine-binding riboswitches may be targets for the development of novel antimicrobial agents. Designed compounds are bound by a purine riboswitches aptamer in vitro with affinities comparable to that of the natural ligand, and several also inhibit microbial growth.
KEYWORDS: Purines, Synthesis
INTRODUCTION:
Purine is a heterocyclic, aromatic, organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature.1
Heterocyclic compounds are organic compounds (containing carbon) that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen, or nitrogen, as part of the ring. Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. Imidazole refers to the parent compound C3H4N2, while imidazoles are a class of heterocycles with similar ring structure but varying substituents.
Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. Two of the four deoxyribonucleotides and two of the four ribonucleotides, the respective building blocks of DNA and RNA, are purines.2
More broadly, the general term purines also is used in reference to derived, substituted purines and their structurally related tautomers (organic compounds that are interconvertible by a chemical reaction).
Prominent purines (derivatives) include caffeine, and two of the bases in nucleic acids, adenine and guanine. In DNA, adenine and guanine form hydrogen bonds with their complementary pyrimidines, thymine and cytosine. In RNA, the complement of adenine is uracil instead of thymine. Purine is also a component in Adenosine triphosphate (ATP), which stores and transports chemical energy within cells.
Purine was named by the German chemist Emil Fischer in 1884. He synthesized it in 1898. Fischer showed that the purines were part of a single chemical family.3
The structure of adenine and guanine, two of the four bases in the DNA molecule, are:
Adenine Guanine
In addition to being biochemically significant as components of DNA and RNA, purines are also found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A.
The quantity of naturally occurring purines produced on earth is huge. Fifty percent (50%) of the bases in nucleic acids, adenine and guanine , are purines. In DNA, these bases form hydrogen bonds with their complementary pyrimidines thymine and cytosine, respectively. This is called complementary base pairing. In RNA, the complement of adenine is uracil (U) instead of thymine1.
Other notable purines are hypoxanthine , xanthine , theobromine , caffeine , uric acid ,and isoguanine .
The name 'purine' (purum uricum) was coined by the German chemist Emil Fischer in 1884. He synthesized it for the first time in 1899[1]. The starting material for the reaction sequence was uric acid, which had been isolated from kidney stones by Scheele in 1776[1]. Uric acid was reacted with PCl5 to give 2,6,8-trichloropurine, which was converted with HI and PH4I to give 2,6-diiodopurine. This latter product was reduced to purine using zinc-dust.
Purines are found in high concentration in meat and meat products, especially internal organs such as liver and kidney. Plant based diets are generally low in purines1.
Examples of high-purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g., Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.
A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran, wheat germ, and hawthorn4.
Higher levels of meat and seafood consumption are associated with an increased risk of gout, whereas a higher level of consumption of dairy products is associated with a decreased risk. Moderate intake of purine-rich vegetables or protein is not associated with an increased risk of gout.[5]
2. Various methods for synthesis of purines
In addition to in vivo synthesis of purines in purine metabolism, purine can also be created artificially. Purine (1) is obtained in good yield when formamide is heated in an open vessel at 170 oC for 28 hours[6]. (scheme 1)
Scheme 1: synthesis of purine from formamide
2.2. Oro, Orgel and co-workers have shown that four molecules of HCN tetramerize to form diaminomaleodinitrile (12), which can be converted into almost all natural-occurring purines[7]. (scheme 2)
Scheme 2: synthesis of various natural purines.
2.3. The Traube purine synthesis (1900) is a classic reaction (named after Wilhelm Traube) between an amine-substituted pyrimidine and formic acid[8]. (scheme 3)
Scheme 3: synthesis of purine from substituted purines
2.4. The new 6- and 7-member tricyclic purine derivatives as shown below were synthesized by intramolecular nucleophilic substitution[9]. (scheme 4)
Scheme 4: synthesis of new 6- and 7- member tricyclic purines from 6- thiopurine.
2.5. Synthesis of O6-alkylguanine derivatives:
The key intermediate 2-amino-6-chloropurine 3 was synthesized by a two-step procedure from commercially available guanine 1[10]. (scheme 5)
Scheme 5: synthesis of 2-amino-6-chloropurine from guanine.
2.6. Toyota et al. reported alkylation of 6-chloropurine with alcohols by Mitsunobu reaction and described the preparation of 9-alkylated adenines. This method is adopted for the synthesis of 2-substituted 9-(2,6-difluorobenzyl)-9H-purines[11]. (scheme 6)
Scheme 6: synthesis of 2-substituted 9-(2,6-difluorobenzyl)-9H-purines from 6- chloro purines.
2.7. Synthesis of novel purine derivatives of L-Ascorbic acid:
These compounds were obtained by a route which involved direct condensation of 6-chloro purine with 5-acetyl-6-bromo-2,3-dibenzyl-L-ascorbic acid (ABDA). This reaction afforded both N-9 and N-7 isomers in a ratio of 4:1. On the contrary, reaction of 6-(N-pyrrolyl)purine with ABDA gave only the N-9 regioisomer. [12] (scheme 7)
Scheme 7: Synthesis of purine derivatives of L-Ascorbic acid.
2.8. Synthesis of N-(Purin-6-yl )amino Acids 3a-h[13]. (scheme 8)
Scheme 8: Synthesis of N-(Purin-6-yl )amino Acids 3a-h.
2.9. Development of Basic Methodologies of Cross-coupling Reactions of Halopurines[14]. A new methodology of perfluoroalkylation of purines has been developed based on modified Hiyama reaction. Thus 6-iodopurines reacted with perfluoroalkylsilanes in the presence of KF and CuI give 6-(perfluoroalkyl)purines[14]. (scheme 9)
Scheme 9: Synthesis of 6-(perfluoroalkyl)purines.
2.10. Efficient methodology for the synthesis of arylpurines by the Suzuki-Miyaura reactions of halopurines with arylboronic acids under Pd catalysis[15]. (scheme 10)
Scheme 10: Synthesis of aryl purines.
5. REFERENCES:
1- Rosemeyer, H. Chemistry & Biodiversity 2004, 1, 361.
2- Fischer, E. Berichte der Deutschen Chemischen Gesellschaft 1899, 32, 2550.
3- Scheele, V. Q. Examen Chemicum Calculi Urinari, Opuscula, 1776, 2, 73.
4- Gout Diet: Limit High Purine Foods
5- NEJM - Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men.
6- Yamada, H.; Okamoto, T. (1972). “A One-step Synthesis of Purine Ring from Formamide”. Chemical & Pharmaceutical Bulletin 20: 623.
7- Ferris, J. P.; Orgel, L. E. Journal of the American Chemical Society, 1966, 88, 1074.
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9- Arturene Maria Lino Carmo, Fenanda Gambogi Braga, Marcio Luiz De Paula, Ana, Paula Ferreira Synthesis and Biological Activity of New Tricyclic Purine Derivatives Obtained by Intramolecular N-7 Alkylation Letters in Drug Design & Discovery, (2008), 5, 1-5.
10- Yu Lin Hu, Qiang Ge, Ming Lu and Hong Fei Lu Bull Chem. Soc. Ethiop. (2010), 24(3) 425 - 432.
11- Shigetada kozai and Tokumi maruyama, Synthesis and Biological Activity of 9- (2,6-Difluorobenzyl)-9H-purines Bearing Chlorine, Chem. Pharm. Bull. (1999), 47(4) 574—575.
12- Silvana Raic-Malic Antonoja Hergold- Brundic, Ante Nagl, Mira Grdisa, Kresimir Pavelic, Eric De Clercq and Mladen Mintas Novel Pyrimidine and Purine Derivatives of L-Ascorbic Acid: Synthesis and Biological Evaluation J. Med. Chem. (1999), 42 2673-2678.
13- Ahmed M. Shalaby, Wahid M. Basyouni and Khairy A. M. EI Bayouki New N-(Purin-6-yl)-amino Acid and –Peptide derivatives; Synthesis and Biological Screening J. Chem. Research (S), (1998) 134-135.
14- Hocek, M.; Holý, A. Collect. Czech. Chem. Commun. (1999), 64 229-241.
15- Havelková, M.; Dvořák, D.; Hocek, M. Synthesis (2001), 1704-1710.
Received on 24.07.2011 Modified on 05.08.2011
Accepted on 14.08.2011 © AJRC All right reserved
Asian J. Research Chem. 4(9): Sept, 2011; Page 1361-1365