Synthesis of certain alkenyl purines and purine analogs

Synthesis of alkenyl derivatives of certain purines and purine analogs is described. Direct alkylation of the sodium salt of 6-chloropurine (1) either with 1-bromo-2-pentene or 4-bromo-2-methyl-2-butene in N,N-dimethylformamide furnished N-7, 4a and N-9, 3a , 3b alkenyl derivatives. Similar alkylation of 2-amino-6-chloropurine (2) provided the corresponding N-7, 4c-4e and N-9, 3c-3e alkenyl derivatives. Acid hydrolysis of these chloro derivatives 3a-3e, 4a,c-e furnished the corresponding alkenyl hypoxan-thines 6a, 6b and 7a or alkenyl guanines 6c-6e and 7c-7e. Treatment of 3a-3d with thiourea in absolute ethanol provided the corresponding 6-thio derivatives 5a-5d. Alkylation of the sodium salt of either purine-6-carboxamide (8) or 1,2,4-triazole-3-carboxamide (10) gave mainly one isomer 9a, 9b and 11a, 11b. The direct alkylation of pyrrolo[2,3-d]pyrimidin-4(3H)-one (12) gave N-3 alkenyl derivatives 13a, 13b , and the N-7 alkenyl derivatives 16a, 16b have been prepared starting from the 4-chloro derivative 14 . Synthesis of 2-amino-7-(2-penten-1-yl)pyrrolo[2,3-d]pyrimidin-4(3H)-one (19a) has been accomplished starting from 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine (17) . These alkenyl derivatives were found to be devoid of anti-HCMV activity in vitro.     

Synthesis of certain alkenyl purines and purine analogs as inhibitors of tumor necrosis factor alpha (TNFα)

The preparation of 2-penten-1-yl and 3-methyl-2-buten-1-yl derivatives of adenine 2a,b , 7-deazaadenine 2c,d , 2-aminopurine 4a,b and 5a,b , 4-aminopyrazolo[3,4-d]pyrimidine 7a,b and 7-amino-v-triazolo-[4,5-d]pyrimidine 8a–10a and 8b-10b is described. The synthesis of compounds 2a-d was accomplished by the functional group transformation reaction, whereas the synthesis of 4a-8a and 4b-8b was performed by the alkylation of the sodium salt of the heterocycles with alkenyl bromides. These alkenyl derivatives prepared as congeners of pentoxifylline (methylxanthine) were evaluated for their anti-tumor necrosis factor a activity in human monocytic leukemia cells. Only compounds 7a and 7b exhibited significant activity and a poor toxicity profile in this assay. In peripheral blood mononuclear cells, compounds 7a and 7b, inhibited tumor necrosis factor a production in a dose dependent manner.     

Synthesis of C-aryl and C-alkyl glycosides using glycosyl phosphates

[reaction: see text] Mannosyl and glucosyl phosphate donors were successfully used in constructing C-aryl linkages common to many natural products via a Lewis acid induced Fries-like rearrangement. The rearrangement was stereo- and regiospecific, yielding only one C-glycoside product. C-Alkyl glycoside carbohydrate mimetics were generated by using silicon-derived C-nucleophiles and glycosyl phosphates.     

Synthesis of 4- and 5-disubstituted 1-benzylimidazoles,important precursors of purine analogs

(Z)-N-(2-amino-1,2-dicyanovinyl)-N'-benzylformamidine 6 has been prepared both from the reaction of benzylisonitrile with the hydrochloride salt of diaminomaleonitrile and from reaction of ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimidate with benzylamine. Based-catalyzed cyclization of amidine 6 led to imidazoles 7 and 8 depending on the reaction conditions. Compound 7 reacts with acetone and butane-2,3-dione to give the 2,2-disubstituted-6-carbamoyl-1,2-dihydropurines 9a and 9b respectively. 2-Methyl-6-carbamoylpurine 12 was obtained from the reaction of imidazole 7 with pentane-2,4-dione. The same compound was observed in the ¹H nmr spectrum of a solution of 1,2-dihydropurine 9b in deuteriochloro-form. Benzylimidazole 7 can be acetylated with acetic anhydride leading to compound 14 . This, in solution, undergoes an acyl migration reaction to give imidazoles 15 and 17 . Imidazole 15 cyclizes in the presence of base to the corresponding 6-cyanopurine 16 . A solution of 14 in methanol is slowly converted into the 6-methoxypurine 18 , possibly via a methoxymidoyl intermediate. A similar intermediate 13 has been isolated from 7 in methanol.     

Synthesis of certain metabolites and analogs of vitamin B6 and their ring-chain tautomerism

Pyridoxol and pyridoxal on benzylation with dimethylphenylbenzylammonium hydroxide (“leucotrope”) gave 3-O-benzylpyridoxol (IV) and 3-O-benzylpyridoxal (V), respectively. As a possible mechanism of this reaction an ion pair intermediate has been postulated. Oxidation of IV and V with chromic oxide-pyridine-acetic acid complex gave 3-O-benzyl-4-pyridoxic acid lactone (VI), which could also be obtained by benzylation of 4-pyridoxic acid. Treatment of VI with dimethylamine gave 2-methyl-3-benzyloxy-5-hydroxymethylpyridine-4-N,N-dimethylcarbox-amide (X) which oxidized to form the 5-formyl derivative (XI). The latter on hydrolysis yielded the metabolite, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylic acid (I). When reacted with liquid ammonia, VI gave 3-O-benzyl-4-pyridoxamide (VII) which was then oxidized to give 2-methyl-3-benzyloxypyridine-4,5-dicarboxylic acid cyclicimide(IX). Acid hydrolysis of IX gave another metabolite, 2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid (XIII), which could also be obtained by oxidizing XI with potassium permanganate in water to yield 2-methyl-3-benzyloxy-5-carboxypyridine-4-N,N-dimethylcarboxamide (XII) and subsequent hydrolysis with hydrochloric acid. A positional isomer of I, 2-methyl-3-hydroxy-4-formylpyridine-5-carboxylic acid (XVII) was synthesized starting from 3-O-benzyl-5-pyridoxic acid lactone (XIV) following similar reaction sequences used for the preparation of I. Ring-chain tautomerism has been studied in I, XVII, opianic acid (XVIII), phthalaldehydic acid (XIX) and (2-carboxy-4,5-dimethoxy)-phenylacetaldehyde (XX) in different solvents by nmr and in the solid state by ir spectroscopy. A direct and reliable differentiation between the open form (aldehyde proton in low field) and the ring form (lactol proton in the intermediate field) has been obtained by nmr spectroscopy. In sodium deuteroxide and pyridine-d₅ the open chain form existed exclusively (except for homolog (XX) which is in cyclic form in pyridine-d₅), whereas in 18% hydrogen chloride in deuterium oxide all the compounds are completely in the cyclic form. In hexafluoroacetone hydrate-d₂, XVIII, XIX, and XX exist in the cyclic form whereas I is in the open form. In DMS0-d₆ both cyclic and open-chain forms have been observed in XVIII, XIX and XX. Definite peak assignment for the two forms could not be made in I due to broadening or superimposition with C₆-H. The metabolite I, isometabolite (XVII) and opianic acid (XVIII) form cyclic acetyl derivatives which give a sharp lactol peak. In the solid state XVIII, XIX are in the cyclic form and I and XX in the open-chain form as observed by ir spectroscopy.     

Aza and deaza analogs of purine nucleosides (review)

Methods for the preparation of aza and deaza analogs of purine nucleosides, viz., nucleosides of imidazo[4,5-d]-v-triazines, imidazo[4,5-b]pyridines, and imidazo[4,5-c]pyridines, and their properties are described. References to the synthesis of nucleosides of imidazo[4,5-d]pyridazines, imidazo[4,5-c]pyridazines, and imidazo[4,5-b]pyrazines are also given.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 147–161, February, 1981.     

Computational design and characterization of new thieno-expanded tricyclic purine analogs

Unnatural nucleobases are under intense research due to their widespread applications in nucleic acids research. In this work, four new thieno-expanded purine analogs comprising ^ttzA, ^tthA, ^ttzG, and ^tthG were computationally designed based on the isomorphic tz- and th-bases. These base analogs can also be seen as modified derivatives of the previously reported tricyclic purine analogs (^ttA and ^ttG). The structural, electronic, and photophysical properties are studied by means of DFT and TDDFT calculations. We find out that these new bases can form stable Watson-Crick base pairs with natural counterparts, thus potentially mimicking natural nucleobases in DNA/RNA duplexes. Calculations reveal that these bases have smaller AIPs and HOMO-LUMO gaps than natural ones, suggesting that they are candidates for applications in nanowire technology. Particularly, the photophysical properties were explored, and the results are compared with those for tz-, th-, and tt-bases. The nature of the low-lying excited states is discussed, and analyses reveal that the thiophene-homologation would not change excitation maxima of ^thA and ^tzA, while it will result in large red-shifts of those of ^thG and ^tzG. Meanwhile, thiophene insertion has relatively larger influences on the emissions ^thA and ^tzG, for which the fluorescence was 37 nm blue-shifted and 19 nm red-shifted, respectively. Taking these new bases as derivatives of ^ttA and ^ttG, it was found that the modifications would result in large red-shifts of both the excitation maxima and the fluorescence. The effects of water solution and base paring on the phtotophysical properties were also considered.     

Synthesis and spectral luminescent properties of certain pyridine and quinoline analogs of isomeric distyrylnaphthalenes and styryl- and distyrylanthracenes

A series of pyridine and quinoline analogs of isomeric distyrylnaphthalenes and styryl- and distyrylanthracenes has been synthesized. Their spectral-luminescent properties were studied. Compounds whose structures are sterically hindered in the ground state have the highest Stokes' shift.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 820–823, June, 1987.     

PMR spectra of certain chalcones and their heterocyclic analogs

The PMR spectra of chalcone and some of its derivatives and heterocyclic analogs have been measured, the signals have been assigned to certain atomic groupings and the trans configuration of the molecules has been established. We show that the conductivity of the electronic effects increases from the furan ring to the thiophene and selenophene rings. The effect of a carbonyl group in heteroaromatic systems on the proton signals from a methyl group in the side chain is markedly less than it is on the proton signals from the ring.     

Syntheses of pyrimidine and purine analogs derived from 1,2,6-thiadiazine 1,1-dioxide

5-Amino-3-oxo-2H, 4H-1,2,6-thiadiazine 1,1-dioxide and the monopotassium salt of 3,5-dioxo-2H, 4H,6H-1,2,6-thiadiazine 1,1-dioxide was obtained by condensation of sulfamide and ethyl cyanacetate and diethyl malonate, respectively. 7-Oxo-1H,4H,6H-imidazo[2,3-c]-1,2,6-thia-diazine 5,5-dioxide was prepared by a multi-step reaction sequence from 5-amino-3-oxo-2H, 4H-1,2,6-thiadiazine 1,1-dioxide.     

New cyclobutyl analogs of adenosine and guanosine. Part 1. Synthesis of the 9-[3,3-bis(hydroxymethyl)cyclobutyl]purine nucleoside analogs

The synthesis of 1-amino-3,3-bis(benzyloxymethyl)cyclobutane has been performed from 3,3-bis(benzyloxymethyl)cyclobutanone, via the corresponding oxime which was reduced with lithium aluminum hydride. The amine thus obtained led to two new cyclobutyl analogs of adenosine and guanosine which were devoid of antiviral activity against HSV-1, HCMV and HIV in cell culture.     

Covalent hydration energies for purine analogs by quantum chemical methods

In this work, covalent hydration energies for a variety of azanaphthalenes and purine analogs have been calculated using a variety of quantum chemical methods. On the basis of these results, we recommend the CPCM(UA0)‐B3LYP/6‐31+G(d,p) level for rapid prediction of covalent hydration energies. However, we caution the use of this methodology for computing covalent hydration energies for fluorine‐containing compounds. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Electronic spectra of 5,6-polymethylenethiapyrylium salts and certain oxygen analogs

Electronic absorption and emission spectra of substituted 5,6-tri- and 5,6-tetramethylenethiapyrylium salts are examined to determine the influence of the degree and character of substitution of the heterocycle, the size of the condensed alicycle, the nature of the heteroatom and the counterion, and the polarity of the solvent.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 198–202, February, 1985.     

Synthesis of phthalascidin analogs

We report a new approach to obtain phthalascidin analogs. 6-Phthalimidomethylpyrazino[1,2-b]isoquinoline-1,4-dione (5a) was obtained in a one-pot N-alkylation/cyclization of the corresponding 1-acetyl-3-arylmethyl-2,5-piperazinedione with N-phthalylacetaldehyde dimethyl acetal. Chemoselective reduction of the C(1)-carbonyl group in the 3-arylmethyl-11,11a-dehydroderivative 9a was followed by cyclization of an acyliminium intermediate, to give the 6,15-imino-7-oxo-14,14a-dehydroisoquino[3,2-b]3-benzazocin 11a. Alternatively, the octacyclic compound 13a was obtained through a novel double cyclization of a precursor in which the C(1)-carbonyl and one phthalimide carbonyl group were reduced.     

Synthesis of methaprogerol analogs

Novel synthetic approaches towards analogs of methaprogerol, the efficient wound healing drug, were developed. Several hitherto unknown compounds obtained exhibited in vivo activity similar to methaprogerol. 2-(3-Dimethylaminopropyl)-5-methylhex-4-enoic acid enhanced the efficacy of the treatment of diseases of various etiologies and different organ injuries by transplantation of mesenchymal stem cells (MSC) and MSC-derived cardiomyoblasts.     

Synthesis of melatonin analogs

Conclusions A number of melatonin analogs, containing dichloroacetic acid and various amino acid residues instead of an acetic acid residue, were synthesized.     

Synthesis of ethophenprox analogs

The synthesis of ethophenprox analogs was performed by condensation of alcohols with benzyl halides under conditions of the phase transfer catalysis. The ultrasonic irradiation was shown to accelerate the reaction and to increase the yield of ethers. The trends in fragmentation of new generation pyrethroids under the electron impact were established. Insecticidal activity of the compounds obtained was evaluated.