9- adenine derivatives, preparation

For the investigation of molecular recognition in micelles, adenine derivatives and positively charged (thyminylalkyl)ammonium salts such as shown in Figure 30 were prepared, which were solubilized in sodium dodecyl sulfate (SDS) solutions. Nmr studies have shown that binding occurs in a 1 1 molar ratio in the interior of the micelles as illustrated in Figure 30 (192). 

The utility of the Zincke reaction has been extended to the preparation of various NAD and NADH analogs. Holy and co-workers synthesized a series of NAD analogs containing nucleotide bases as a means to study through-space interaction between the pyridinium and base portions. Nicotinamide-derived Zincke salt 8 was used to link with various adenine derivatives via tethers that contained hydroxyl (105 —> 106, Scheme 8.4.35), phosphonate (107—>108, Scheme 8.4.36), and carboxylate "... 

Aldehydo nitriles are readily available and can be used to prepare 4-amino-6-unsubstituted pyrimidines carrying one or more substituents in any of the other positions. Equivalents of the formyl group are also often used, for example, a 3-ethoxy-, 3-amino-, or 3-haloacrylonitrile. Most syntheses with /3-keto nitriles are carried out with equivalents thereof Such equivalents are /3-substituted /3-alkoxy-, /3-amino-, or /3-haloacrylonitriles. /3 -Ester nitrile reactions are also well established. Malononitriles and substituted malononitriles react readily with thiourea and N-substituted thioureas in refluxing ethanolic sodium ethoxide to form pyrimidine-4,6-diamines. An example is the reaction of N2-malononitrile 680 with N2-thiourea 681 to give N4- 4,6-diamino-2-(l//)-pyrimidinethione 682 which was then used in the synthesis of Ns-labeled adenine derivatives <2001JOC5463>. 

With the development of the cross coupling methodology, many 6-C-substituted purines have been prepared in the past decade. Thus, 6 halopurine derivatives react with arylmagnesium halides,25 alkyl(aryl)zinc or tin reagents,26 trialkylaluminum,27 or alkylcuprates28 to give the 6-alkylpurine derivatives. Also a reverse approach based on the reaction of purine-6-zinc iodide with aryl or vinyl halides has recently been described.29 For the synthesis of 6-arylpurines, an alternative approach makes use of radical photochemical reactions of adenine derivatives with aromatic compounds,30 but this method is very unselective and for substituted benzenes, mixtures of ortho-, meta-, and para substituted derivatives were obtained. 

Substituted 4(5)-aminoimidazole-5(4)-carbonitriles are versatile starting materials for the synthesis of purine ring systems. The combination of an electrophilie cyano group proximate to a nucleophilic amino function results in a one-step addition-cyclization reaction of electrophiles to give purine analogs. Triethyl orthoformate is widely used for the preparation of adenine and adenine derivatives without a substituent at C2. 

N NMR spectroscopy was used to study the tautomerism of adenine derivatives enriched by the N-15 isotope." These enriched samples were prepared as probes for further biochemical studies. While tautomeric mixtures of N -H and N -H were reported for adenine and 2-MeS-adenine based on the " N NMR spectra, an N -H species was suggested for the solution of S-Br-adenine. These observations were supported by quantum chemical calculation of the individual tautomeric forms for isolated molecules and for the inclusion of solvent effects (both continuum and discrete models). 

The chloromercuri procedure has also been utilized to prepare the ribonucleosides of 6-methylthiopurine, 6-methylpurine, a number of adenine derivatives, " 8-azapurines, and imidazo[4,5-d]pyrazines. ... 

A nucleotide base-imprinted polymer membrane has been reported in which methacrylic acid was used as a functional monomer for the imprinting of an adenine derivative, 9-ethyladenine [41], A free-standing film was prepared by polymerizing a DMF solution containing methacrylic acid and ethylene glycol dimethacrylate on a silanized glass slide at 65-70 °C under nitrogen atmosphere. 

Some groups have introduced fluorescent base analogs that replace a normal base (Fig. 4.35) to monitor the local dynamics of DNA [232, 335, 337-340, 345], 2-Aminopurine and the d5 base are closely related to the natural DNA bases adenine and thymine and can replace A or T in the double helix the coumarin derivative prepared by R. Coleman [345] occupies the space of an entire base pair [232]. 

The synthetic strategies for 100 are divided into two categories (A) the stereoselective preparation of 2-fluorofuranose and the coupling with an adenine derivative and (B) the stereoselective fluorination at C2 of the furanosyl adenine. 

Aminophosphines. The synthesis and use of aminophosphines as ligands have been reviewed. Raeemie ehlorophosphines of the type R R PCl have been shown to react stereoselectively with chiral amines (1-phenylethylamine or aminoacid esters) in the presence of triethylamine to give the diastereomerically enriched aminophosphines (137), which were isolated as diastereomerically pure crystalhne borane complexes. This approach has also been used in the synthesis of chiral t-butylphenylphosphine oxide, via the acid hydrolysis of an intermediate chiral aminophosphine. Among other new mon-oaminophosphines prepared by treatment of primary or secondary amines with ehlorophosphines in the presence of a base are the adenine derivatives (138), the phosphinoalkylaminophosphines (139), " the aminophosphine-phosphine... 

Early in vivo studies with bacterial suspensions indicated that purines exerted a profound inhibitory effect on an early enzyme of the pathway [39-41]. The nature of the inhibitor could not be readily determined because of the interconversion reactions in the whole-cell preparations. The use of special mutants deficient in certain interconversion steps implicated an adenine derivative as the effector in one case [42] and a guanine derivative in another [33]. Axiomatic inference suggested that the feedback-inhibited enzyme should be the first unique enzyme in the pathway, the glutamine-dependent PRPP amidotransferase (EC 2.4.4. 

A series of carbocyclic analogues of puromycin have been prepared, e.g. (13), derived from stereoisomers of l-amino-3-azido-2,4,5-trihydroxycyclo-pentane and 4-chloro-pyrimidine precursors, and similarly carbocyclic analogues of uridine and thymidine were made from 1-amino tetrahydroxy-cyclopentanes and nitrourea. A number of 9-(3-amino-2,4-dihydroxycyclo-pentyl)-adenine derivatives have been obtained from a bicyclic cyclopentene... 

A simple two-stage conversion of nucleosides to their corresponding 5-deoxy nucleosides involves sequential treatment with thionyl chloride in HMPT, giving the 5 -chloro-5 -deoxy derivatives which were then reduced with tri-butyltin hydride and a,a -azobis(isobutyronitrile) in dry THF. In this way 5 -deoxyadenosine, 5 -deoxyuridine, 5 -deoxythymidine, 5 -deoxytoyomycin, 5 -deoxysangivamycin, 2, 3, 5 -trideoxyadenosine, 3 5 -dideoxyadenosine, and 9-(5 -deoxy-jS-D-arabinofuranosyl)adenine were prepared. ... 

Using a reaction sequence involving dibutylstannylation and displacement of triflate, new 2 -substituted-2 -deoxyarabinofuranosyl adenine derivatives have been prepared (Scheme 12) the products (92) and (93) were converted into the corresponding 2 -amino- and 2 -thio-ara6mo-nucleosides. A communication, with no synthetic details, on the preparation and use of 2 -azido-and 2 -amino-2-deoxy-j8-D-arabinofuranosyl cytidine as cytotoxic agents has been published. ... 

Holy (77) described the preparation of 9-(beta-D-ribofuranosyl)-2-hydroxypurine beginning with the reaction of 5-aminocytosine with ethyl orthoformate involving several intermediates and reactants including 2-hydroxypurine and 5-nitrocytosine their TLC and on silica with chloroform and chloroform-ethanol (1 40). A (78) 9-(RS)-(2,3-dihydroxypopyl)adenine derivative has been outlined for the preparation, separation, and identification of isomeric 3-aminopropylamino and its derivatives by comparison to known substances on silica by using several solvents including 2-propanol-NH3-water, chloroform-ethanol, and chloroform-methanol. 

Deoxy-3 -iodo-nucleoside derivatives (prepared as described on p. 159) have been converted into 9-(2,3-dideoxy- -D- /ycera-pent-2-enofuranosyl)adenine, via the corresponding 2 -methanesulphonates, and related unsaturated nucleosides. - Details of the preparation of 9-(5-hydroxymethylfuran-2-yl)adenine (see p. 159) and 9-(2-deoxy-D-er> /Aro-pent-l-enofuranosyl)adenine (see Vol. 8, p. 145) have also been published. ... 

Water soluble nucleic acid analogs were prepared by grafting uracil, thymine, 5-fluorouracil, hypoxanthine, cytosine, and adenine derivatives containing a hydroxy group onto linear poly(ethyleneimine). These polymers contained about 90 unit% of the nucleic acid bases, and were easily soluble in water at neutral pH resign. The analogs were found to form complementary polymer complexes with each other and with polynucleotides. The interaction study was made on these polymers, and with polynucleotides poly(uridylic acid) poly(U), poly(adenylic acid) poly(A), poly(inosinic acid) poly(I) and poly(cytidylic acid) poly(C) in water. They were found to form polymer complexes with polynucleotide by specific base-base interaction in aqueous solution. 

In the present study, water soluble poly(ethyleneimine) derivatives containing uracil, thymine, 5-fluorouracil, hypoxanthine, cytosine, and adenine were prepared and their interactions with polynucleotides, such as poly(A), poly(U), poly(C), poly(I) in natural aqueous solution were investigated. As 5-fluorouracil is known as a famous anticancer agent, it seems to be interest to study the interaction of the polymer containing 5-fluorouracil unit with polynucleotides. The bioactivity of the polymer complex of nucleic acid analogs with polynucleotides will be reported... 

Tetrahydrofuranyl derivatives of uridine and 2 -deoxycytidine, either partially or completely O- and/or N-substituted, have been prepared from the nucleoside with dihydrofuran. The protecting group may be removed either by dilute acid or by treatment with microsomal non-specific oxidases. 3 -0-tetrahydrofuranyl-N-benzoyladenosine and a 5 -0-dimethoxytrityl-arabinosyl-adenine derivative have been prepared conventionally for use in ribo-oiigonucieotide synthesis. 

The PLL derivatives containing nucleic acid bases were prepared according to reference 21. Polymer (18) (PLL-Thy-COOH) containing pendent thymine base was obtained from the reaction of (17) reacted with activated ester of thymine derivative. In the case of the adenine derivative, the amino group in adenine base was protected by a diphenylphosphyno-thioyl (Ppt) group,because the activated ester derivative was unstable. The molar ratios of the thymine and the adenine units to PLL in the polymers were 0.94 and 0.73, respectively, determined by NMR spectroscopy. 

Alternatively, a resin having adenine derivatives bonded by silanol bonding (Si-O-Si-PLL-Ade 9 ) was prepared as follows The terminal carboxyl group of the polymer (HBr PLL-Ade-COOH) was silanized by the treatment with 3-aminopropyltriethoxysilane, followed by reaction with silica gel (LiChrosorb Si 1000, Merck). Immobilization of the PLL derivatives on silica gel was confirmed by IR spectroscopy and the content of the polymer in the silica gel derivatives were determined by elementary analysis. 

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