[Enhancing the stability of oligonucleotide duplexes. The effect of adding 1-(2'-deoxy-beta-d-ribofuranosyl)-5-nitroindole]. / Povyshenie stabil'nosti dupleksov oligonukleotidov. Effekt prisoedineniia 1-(2'-dezoksi-beta-d-ribofuranozil)-5-nitroindola.

We studied the properties of DNA duplexes containing 5-nitroindole (N) in one of the chains. We synthesized 8-membered oligos with N at the 5' or at the 3' end: 5'-d(NXGACCGTC)-3' or 5'-d(GACCGTCXN)-3', where X is one of the four natural bases, making all four kinds of oligos with and without N. We also prepared 11-membered oligos complementary to the above octanucleotides: 5'-d(TGACGGTCYZT)-3' and 5'-d(TZYGACGGTCT)-3', where Y and Z are A, G, C, or T. The stability of duplexes obtained with these oligos was assessed by melting, and the thermodynamic parameters delta H, delta S, and Tm were calculated. Comparison of the melting curves for modified and nonmodified duplexes demonstrated that the presence of N at the 5' end of one chain raises the Tm by 6.6 degrees C on average; if N is at the 3' end of the same chain, the Tm increases by about 3 degrees C.

[Ligands with specific affinity to a specific sequence of DNA base pairs. XI. The synthesis and binding to DNA of bis-netropsins with the C-ends of their netropsin fragments tethered by tetra- or pentamethylene linkers]. / Ligandy, spetsifichnye k opredelennym posledovatel'nostiam par osnovanii DNK. XI. Sintez i sviazyvanie s DNK bis-netropsinov, v kotorykh netropsinovye fragmenty soedeneny mezdu soboi po C-kontsam tetra- i pentametilenovymi zven'iami.

Bis-Netropsins with the C-ends of their netropsin fragments tethered via tetra- or pentamethylene linkers and with Gly or L-Lys-Gly residues on their N-ends were synthesized. The footprinting technique was used to study the specificity of bis-netropsin binding to the specially constructed DNA fragments containing various clusters of A.T pairs. It was found that the linker length affects the binding of bis-netropsins, with the tetramethylene linker providing better protection than the pentamethylene linker. It was shown that the newly synthesized bis-netropsins bind tighter to the 5'-A4T(4)-3' sequence, whereas the bis-netropsin with a linker between the netropsin N-ends binds better to 5'-T4A(4)-3' sequences. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 6; see also http://www.maik.ru.

Three-stranded clip of the oligonucleotide 5'-(dT)10pO(CH2CH2O)3p(dT)10pO(CH2CH2O)3p(dA)10-3'.

Temperature dependence of UV and CD spectra of the oligonucleotide 5'-(dT)10-L-(dT)10-L-(dA)10-3' [tripl(ATT)] [L = -pO(CH2CH2O)3p-] in phosphate buffer, pH 7, at various NaCl concentrations and in the presence or absence of 0.01 M MgCl2 has been studied. At low oligonucleotide concentrations (2.2 x 10(-5) M nucleotide concentration) all structural transitions proceed intramolecularly. Tripl(ATT) exists in three forms: as a three-stranded clip (at low temperatures), a double-stranded hairpin (at intermediate temperatures), and as an open strand (at high temperatures). Thermodynamic parameters of the triplex formation depending on the NaCl concentration were calculated. The CD spectra were assigned to the single-, double-, and three-stranded forms. Ethidium bromide (EtBr) binding to the three-stranded clip was studied. Ethidium bromide molecules were shown to intercalate into the triple helix with the stable complex formation (association constant is 10(6)). One molecule of three-stranded clip binds not more than three EtBr molecules. The proposed synthetic model (oligonucleotide blocks coupled by hydroxyalkyl chains) has been shown to be convenient for studies of the physical and chemical properties of the triplex and other multistranded complexes of DNA.

[Compounds, similar to acyclovir. VIII. Synthesis and antiviral activity of (R/S)-5-hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of nucleic bases]. / Soedineniia, podobnye atsikloviru. VIII. Sintez i protivovirusnaia aktivnost' (R/S)-5-gidroksi-4-gidroksimetil-3-oksapent-2-il'nykh proizvodnykh nucleinovykh osnovanii.

The (R/S)-5-hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of the uracil, thymidine, cytosine, adenine, guanine and 1,2,4-triazol-3-carboxamide were synthesized using 1,3-diacetoxy-2-(1-acetoxy)propane and 1,3-dichloro-2-(1-chlorethoxy)propane as alkylating agents. The guanine derivatives exhibited activity against HSV-1 (chemotherapeutic index 32).

[A triple-stranded "clip" from the oligonucleotide 3'-(dA)10-pO(Ch2Ch2O)3p-(dT)10-pO(CH2CH2O)3-p-(dT)10(-5)]. / Trekhtsepochechnaia "skrepka" iz oligonukleotida 3'-(dA)10-pO(CH2CH2O)3p-(dT)10-pO(CH2CH2O)3p-(dT)10(-5).

The temperature dependence of the UV- and CD-spectra of the oligonucleotides 3'-d(A)10-L-(T)10-5' [anti(AT)], 3'-d(A)10-L-d(T)10-3' [par(AT)] and 3'-d(A)10-L-(dT)10-L-(dT)10-5' [tripl(ATT)] (L = -PO(CH2CH2O) 3p-) in the phosphate buffer at pH 7 under different concentrations of NaCL and in the presence or absence of 0.01 M MgCl2 was studied. All registered structural changes are the result of intramolecular processes if the concentrations of the oligonucleotides is low (about 2.2.10(-5) M). Par(AT) and anti(AT) exist in the only two forms, transforming into each other: under low temperatures they exist as hairpins with the parallel or antiparallel orientation of chains accordingly which transform into unfolded chains when the temperature increased. In contrast trip(ATT) exists in the three different forms depending on the temperature and ion conditions. They are: the three- stranded clip, the two-stranded hairpin with a single stranded "tail" and completely unfolded chain. For the first time this work presents thermodynamic parameters of the triplex formation from deoxyoligonucleotides depending on NaCl concentration. We have registered the CD spectra to one-, two-, and three-stranded forms. Ethidium bromide binding to three-stranded "clip" was investigated, and it was established that molecules of the dye may intercalate into the "clip" with formation of stable complexes (the constant of association 10(6) M-1). It is maximum three molecules of ethidium bromid which may bound to one molecule of the three-stranded clip. It has been shown that the suggested synthetic model (three oligonucleotide blocks combined by hydroxyalkyl chains) is the most convenient for physico-chemical investigations of triplexes today.

[Ligands possessing affinity to specific DNA base pair sequences. IX. Synthesis of netropsin and distamycin A analogs having sarcolysin residues or a platinum(II) atom]. / Ligandy, obladaiushchie srodstvom k opredelennym posledovatel'nostiam par osnovanii DNK. IX. Sintez analogov netropsina i distamitsina A, soderzhashchikh ostatok sarkolizina ili atom platiny(II).

In search for compounds capable of forming covalent bonds with DNA AT-pair clusters, distamycin A and netropsin analogues containing DL-sarcolysin or platinum (II) atom at the N-terminus of the molecule were synthesized, as well as bis-netropsin and bis-distamycin in which two netropsin- or distamycin-like fragments are bound via a cis-diammineplatinum (II) residue. It is shown that these substances can be used for the DNA selective cleavage.

Parallel double stranded helices and the tertiary structure of nucleic acids.

Thermal denaturation of four oligonucleotides, viz. 3'-d(AT)5pO(CH2)6Opd(AT)5-3'(par(AT], 3'-d(AT)5pO(CH2)6Opd(AT)5-5'(anti(AT],3'-d(A)10pO(CH2) 6Op(T)10-3'(par(A-T], and 3'-d(A)10pO(CH2)6Opd(T)10-5' (anti(A-T], was studied in 0.01 M phosphate buffer, pH 7, in the presence of 0.1, 0.25, 0.5 and 1.0 M NaCl. All the oligomers were found to exist at a lower temperature (0 to 20 degrees C) as complexes composed either of two oligomer molecules (a canonical duplex) or of more oligomer molecules whereas, at a higher temperature (30 to 70 degrees C), they formed hairpins with a parallel (par(AT) and par(A-T] or antiparallel (anti(AT) and anti(A-T) orientation of the chains. Melting curves (A260(T] were used to calculate thermodynamic parameters for the formation of hairpins and "low-temperature" duplexes. Experiments on ethidium bromide binding to the oligonucleotides have shown that the oligomer anti(A-T) exists, at a low ionic strength, as a four stranded complex ("quadruplex") contains two antiparallel helices, d(A).d(T), which have a parallel orientation and are bound to one another owing to the formation of additional hydrogen bonds between nucleic acid bases. The possible biological function of quadruplexes is discussed.

[Compounds similar to acyclovir. VI. Synthesis of optically active 1',2'-seconucleosides]. / Soedineniia, podobnye atsikloviru. VI. Sintez opticheski aktivnykh 1',2'-sekonukleozidov.

A convenient method is suggested of synthesis of (3R, 4R)-, (3S, 4S)- and (3R/S, 4S/R)-dihydroxy-3-hydroxymethyl-2-oxapentyl derivatives of the, cytosine, uracyl, adenine and guanine ("full" acyclic analogues of nucleosides with C1'-C2' bond cleaved) by condensation of trimethylsilyl derivatives of nucleic bases (sodium salt in case of adenine) with (3$, 4R)-, (3S )-, (3S, 4S)- and (3R/S, 4S/R)-4,5-diacetoxy-3-acetoxymethyl-1-chloro-2-oxapentanes without catalyst followed by deacetylation.

[Compounds similar to acyclovir. VII. Attempts to construct an anti-herpetic agent (6-hydroxy-2-oxa-4-hexenyl derivatives of nucleic bases]. / Soedineniia, podobnye atsikloviru. VII. Popytka konstruirovaniia protivogerpeticheskogo preparata (6-gidroksi-2-oksa-4-geksenil'nye proizvodnye nukleinovykh osnovanii.

Based on the available data on the acyclovir's mechanism of action we attempted to predict the antiherpetic activity of 6-hydroxy-2-oxahexen-4-yl derivatives of nucleic bases. In terms of this model 9-(6-hydroxy-2-oxahexen-4-yl) guanine might be active. 6-Hydroxy-2-oxahexen-4-yl derivatives of adenine, guanine, cytosine, thymine, uracil, 1,2,4-triazole-3 and 1,2,4-triazole-5-carboxamide have been synthesized and their activity against herpes virus I investigated. The guanine derivative proved to possess rather high activity (chemotherapeutical index 8).

Parallel double helices of DNA. Conformational analysis of regular helices with the second order symmetry axis.

We have performed a conformational analysis of DNA double helices with parallel directed backbone strands connected with the second order symmetry axis being at the same time the helix axis. The calculations were made for homopolymers poly(dA).poly(dA), poly(dC).poly(dC), poly(dG) poly(dG), and poly(dT).poly(dT). All possible variants of hydrogen bonding of base pairs of the same name were studied for each polymer. The maps of backbone chain geometrical existence were constructed. Conformational and helical parameters corresponding to local minima of conformational energy of "parallel" DNA helices, calculated at atom-atom approximation, were determined. The dependence of conformational energy on the base pair and on the hydrogen bond type was analysed. Two major conformational advantageous for "parallel" DNA's do not depend much on the hydrogen-bonded base pair type were indicated. One of them coincided with the conformational region typical for "antiparallel" DNA, in particular for the B-form DNA. Conformational energy of "parallel" DNA depends on the base pair type and for the most part is similar to the conformational energy of "antiparallel" B-DNA.

[Parallel double helix and tertiary structure of nucleic acids]. / Parallel'nye dvoinye spirali i tretichnaia struktura nukleinovykh kislot.

The thermal denaturation of four oligonucleotides, viz. 3'-d(AT)5pO(CH2)6Opd(AT)5-3' (parAT), 3'-d(AT)5pO(CH2)5Opd(AT)5-5' (antiAT), 3'-d(A)10pO(CH2)6Op(T)10-3' (parA-T) and 3'd(A)10pOX X (CH2)6Opd(T)10-5' (antiA-T) in 0.01 M phosphate buffer at pH 7 in presence 0.1, 0.25, 0.5 and 1.0 M NaCl have been studied. It was shown that at lower temperature (0-20 degrees C) all oligomeres exist as complexes of two (canonic duplex) or four (eight) molecules of oligonucleotides, but at higher temperature (30-70 degrees C)- as hairpins with parallel (parAT and parA-T) of antiparallel (antiAT and antiA-T) orientation of chains. Thermodinamic parameters of separated strands-hairpins and hairpins--"low temperature complexes" transition were computated from the melting curves [A260 (T)] by nonlinear regression. AntiA-T was shown by ethidium bromide binding to exist at low strength (0.01 M phosphate buffer without NaCl) as four-stranded complex from two antiparallel double stranded helices parallely oriented and bonded by satisfy hydrogen-bond of groups not involved in WC-pairing. At higher ionic strength the two of such tetramers was conjugated by hydrophobic interaction into octamers. We speculate that four-stranded complexes serves to bring together, and zipper up two antiparallel double stranded helices at replication of DNA, cross-over of gomologues chromosomes and other biochemically important processes.

[Compounds, similar to acyclovir V. Synthesis and antiviral activity of carbethoxyalkoxymethyl derivatives of nucleic bases]. / Soedineniia, podobnye atsikloviru V. Sintez i protivovirusnaia aktivnost' karbétoksialkoksimetil'nykh proizvodnykh nukleinovykh osnovanii.

Ethyl esters and amides of carboxymethoxy-, alpha- and beta-carboxyethoxy- and gamma-carboxypropoxymethyl derivatives of adenine, guanine, cytosine, uracil, thymine, 1,2,4-triazole-3- and -5-carboxamide were synthesized and their antiviral activity was studied.

[Parallel DNA double helices. II. Conformational analysis of regular helices having a second order axis of symmetry]. / Parallel'nye dvoinye spirali DNK. II. Konformatsionnyi analiz reguliarnykh spiralei, imeiushchikh os' simmetrii vtorogo poriadka.

Conformational analysis of double helices of DNA with parallel arranged sugar-phosphate chains connected by twofold symmetry has been performed. Homopolymers poly(dA).poly(dA), poly(dC).poly(dC), poly(dG).poly(dG) and poly(dT).poly(dT) were studied. For each of the homopolymers all variants of H-bond pairing were checked. The maps of closing of sugar-phosphate backbone were previously computed. By the optimization of potential energy the dihedral angles and helix parameters of relatively stable conformations of parallel stranded polynucleotides were calculated. The dependence of conformational energy on the nucleic base character and the base pair type were studied. Two main conformational regions for favourable "parallel" helix of polynucleotides were found. The former of these two regions coincide with the region of typical conformational parameters of B-DNA. On an average the conformational energy of "parallel" DNA is close to the energy of canonic "antiparallel" B-DNA.

Parallel stranded DNA with AT base pairing.

The concentration and temperature dependences of the UV and CD spectra of the oligonucleotide 3'-d(ApTpApTpApTpApTpApTp)-O(CH2)6O-5'-d(pApTpApTpApTpApT pApT) (eicosamer) in aqueous solution at pH 7 in the presence of 0.5 M NaCl were studied. At less than 10(-6) M, the eicosamer was shown to form in solution a hairpin with parallel orientation of chains (parallel hairpin). From thermal denaturation profiles [A260(T)] the thermodynamic parameters, delta H degrees, delta S degrees and Tm for parallel hairpin formation were calculated to be -90 +/- 8 kJ/mol. -300 +/- 20 J.mol-1.K-1 and 40.5 degrees C, respectively. The CD spectra of the parallel double helix differed from those of B-form DNA and had characteristic features: decreasing magnitude of the positive maximum at 265 nm and a negative peak at 285 nm.

[The structure and antiviral activity of ribavirin analogs. I. Molecular and crystal structure of 1-(2-hydroxyethoxymethyl)-1,2,4-triazole-5-carboxamide]. / Struktura i protivovirusnaia aktivnost' analogov ribavirina. I. Molekuliarnaia i kristallicheskaia struktura 1-(2-gidroksiétoksimetil)-1,2,4-triazol-5-karboksamida.

The crystal and molecular structures of the antiviral compound 1-(2-hydroxyethoxymethyl)-1,2,4-triazole-5-carboxamide has been determined by the X-ray diffraction method. The space group is P2i/c, unit cell parameters a = 4,381, b = 18,679, c = 10,776 A, beta = 107,40 degrees, Z = 4. The structure was solved by the direct method and refined by a full-matrix least-squares procedure to R = 4.9%. Two planar groups of atoms can be distinguished in the molecule. The first group involves the atoms of triazole ring, C6, and C1', the second one contains C5, C6, O6 and N6 atoms. The angle between these planes is 5.6 degrees. The carboxyamide group is rotated by 180 degrees in comparison with this group in ribavirin. That is why the intramolecular hydrogen bond C1'-H1'. 1...O6 can form. Torsion angle O5'-C5'-C4'-O4' is 73.9 degrees and it corresponds to gauche-rotamer. The conformation about O4'-C4' bond is trans. The C1'-C4' bond is approximately perpendicular to the aglycone.

[Compounds similar to acyclovir. III. Synthesis of acyclic analogs of 5'-deoxynucleosides]. / Soedineniia, podobnye atikloviru. III. Sintez atsiklicheskikh analogov 5'-dezoksinukleozidov.

A convenient method has been proposed for the synthesis of 1,2-dihydroxy-4-oxahex-3-yl and 1-hydroxy-4-oxahex-3-yl derivatives of guanine, adenine, thymine and cytosine, acyclic nucleoside analogues lacking the 3'--4' bond.

[Synthesis and properties of acyclic analogs of ribavirin]. / Sintez i svoistva atsiklicheskikh analogov ribavirina.

Acyclic analogues of ribavirine, viz. 1-(1-hydroxy-4-oxahex-3-yl)-, 1-(1-chloro-4-oxahex-3-yl)-, 1-(1,2-dihydroxy-4-oxahex-3-yl)-, 1-(1,6-dihydroxy-4-oxahex-3-yl)-, 1-(1-chloro-6-hydroxy-4-oxahex-3-yl)-, and 1-(1,2,6-trihydroxy-4-oxahex-3-yl)-1,2,4-triazole-3-carboxamide, with the C3'-C4' bond of the furanose ring cleaved, have been prepared by condensation of trimethylsilyl derivatives of 3-ethoxycarbonyl-1,2,4-triazole with alkylating agents in the presence of SnCl4 followed by treatment with methanolic ammonia. Convenient methods for synthesis of the alkylating agents were elaborated.