Hydrophilic polymers containing chiral nucleic acid base pendants as polynucleotide analogs

Overberger, C. G.; Brandt, K. A.; Kikyotani, S.; Ludwick, Adriane G.

doi:10.1007/bf00254354

Cited by 13 publications

(3 citation statements)

References 11 publications

(4 reference statements)

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“…We have effectively prepared a carboxylated version of the PVam polymers by free-radical polymerization of dehydroalanines ll-14. (16,17) These monomers are made by coupling the 2-nucleopropionic acids with 8-chloroalanine methyl ester hydrochloride using N,N'-dicyclohexylcarbodiimide in DMF, with the addition of N-hydroxybenzotriazole as a racemization-suppressing agent if the pendant is optically active. Dehydrochlorination of the product is effected with triethylamine; both dehydrochlorination and hydrolysis to the acid salt occur in aqueous NaOH.…”

Section: Resultsmentioning

confidence: 99%

Hydrophilic polymers of ordered conformation-nucleic acid models

Overberger¹,

Brandt²,

Kikyotani³

et al. 1984

Pure and Applied Chemistry

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Nucleic acids contain severa' characteristic structural features: a chiral center adjacent to the base, a stereoregular, hydrophilic poly(phosphate-ribose) backbone which is negatively charged at neutral pH, and a helical secondary structure arising from conformational preferences enforced by base-stacking. We have prepared and studied several synthetic polynucleotide analogs having linear poly(ethylenimine), poly(vinylamine), and poly(dehydroalanine) backbones containing chiral nucleic acid base pendant groups attached through amide bonds. This amide bond increases structural order through its partial double bond character, resulting in restricted rotation of the pendant. Through study of model compounds and from UV, CD, and NMR spectroscopy, we have obtained considerable evidence for polynucleotide-like ordered conformations in these polymers. In addition, several of the polymers have shown antiviral activity in cell culture tests.I NTRODUCT ION 1acromolecules have demonstrated a wide range of biological activity.(l,2) Antitumor, antiviral, interferon-inducing, immunoadjuvant, and other properties are characteristic of some macromolecules. Because of their high molecular weight, they have several potential advantages over conventional low molecular weight agents: sustained activity, greater specificity of action, lower toxicity, reduced undesirable side effects, and more direct use of the polymer-associated active agent.(3) Some of these advantages have been realized, but much more work is necessary if this great potential is to be fulfilled. Of primary importance in this regard are detailed studies of the effects of polymer structure on activity. While structure-activity studies are common in developing low molecular weight drugs, the comparatively new field of polymeric drugs needs many more such investigations. This becomes particularly significant since a polymeric agent possesses more potential structural variables than a conventional small molecule. Systematic study of closely related compounds can provide both an explanation for observed activity and a clear rationale for further synthetic design.Our synthetic program turned towards the study of polynucleotide analogs, both for their value as models of nucleic acids and for their biological properties. Considerable attention has been given to these analogs; this includes both:the homopolymers with polyphosphate backbones, most closely resembling natural nucleic acids, as well as nucleic acid models where the backbone is other than polyphosphate and/or the pendant groups have been modified.(4-6) There have only been a limited number of studies on the biological activity of the nucleic acid models with backbone and/or pendant group modification. (7) As an example of one of the more well-studied systems, poly(9-iinyladenine) has been found to inhibit the replication of Friend leukemia virus in mice:.It does not inhibit the replication of Semliki forest virus (a non-leukemia virus). A similar result was found in a cell culture test studied prior t...

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Section: Resultsmentioning

confidence: 99%

Hydrophilic polymers of ordered conformation-nucleic acid models

Overberger¹,

Brandt²,

Kikyotani³

et al. 1984

Pure and Applied Chemistry

Self Cite

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“…provides the wrong addition of N6-2'-hydroxyethyladenine to polymer 13 and gives eventually, after the usual work-up of the resulting polymer, the acidic units 6 the complete conversion of 13 into 15 (the triester structure) was obtained. In the subsequent step the blocking group was removed quantitatively.…”

Section: Polyphosphates Bearing N-substituted Adenine In the Side Chainmentioning

confidence: 98%

“…The high molecular weight poly(l,3-propylenephosphate) (6) is a solid rubbery product, soluble and stable in water solution. Sometimes it crystallizes during precipitation from solution and its water solubility decreases, apparently due to the formation of the strong intermolecular hydrogen bonds.…”

Section: Ohmentioning

confidence: 99%

Polymerization of Cyclic Monomers Containing Phosphorus

Penczek

Łapienis

Kłosiński

1986

Phosphorous and Sulfur and the Related Elements

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The mechanism of polymerization is discussed, in which cyclic esters of phosphoric acid, and related compounds are converted into linear macromolecules, modelling nucleic and teichoic acid backbones. Structures like deoxyribose polyphosphate and glycerol polyphosphate were prepared from the corresponding cyclic compounds.These polymerizations involve heterolytic breaking of the P-0 bond in the corresponding cyclic monomer and proceed by ionic mechanisms. Both 5-and 6-membered monomers have been polymerized. The thermodynamic parameters of the ring-chain interconversion were determined; the 5-membered ring polymerization is driven by the exothermicity of the ring-opening, whereas polymerization of several 6-membered rings is endothermic and allowed because of the positive change of entropy.Anionic polymerization, and particularly the coordinate-anionic polymerization provides, in contrast to the cationic processes, high-molecular weight polymers with more uniform structure. Anionic polymerization proceeds mostly (in the applied conditions) on the macroion-pairs. The elementary reactions consist of the nucleophilic attack of the paired macroanions on the phosphorus atom in the cyclic monomer molecule. Rate constants of the elementary reactions for the model monomers are discussed.

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Calorimetric studies of the polynucleotide analog poly(−)2‐[2‐(thymin‐1‐yl) propanamido]propenoic acid

1986

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SynopsisThe thermally elicited structural and conformational transitions of the polynucleotide analog, poly(-)-2-[2-(thymin-l-yl)propanamido]propenoic acid, P(-YTDHA, have been studied using differential scanning calorimetry (DSC), differential thermal analysis (DTA), and thermogravmetric analysis (TGA). The differential scanning calorimetry curves obtained on solid P(-)TDHA samples exhibited five distinct transitions. The transition occurring at 50°C is attributed to a disruption of interactions involving thymine-thymine stacking. In contrast the transition observed at 83°C is attributed to a hydrogenbonding interaction involving the thymine residues, whereas the transition occurring at 110°C is assigned to hydrogen bonding of the carboxylic acid sidechain groups. The transitions observed at 50, 83, and 110°C are reversible if the heated and quenched sample is allowed to equilibrate in an atmosphere of high humidity. The transition occurring at 127°C is viewed as a structural rearrangement of the polymer backbone that does not involve the participation of water molecules. The transition observed at a temperature above 197°C is attributed to a structural modification of the polymer resulting from decomposition. Solutions of P(-)TDHA in 0.1M phosphate buffer a t pH 7.05 showed only a single transition at 50"C, which is in accord with an observed transition in the solid state assigned to the disruption of base-stacking interactions. The average enthalpy for the transition at 50°C was 0.92 cal/g in the solid state and 1.08 cal/g for the solution, which provides additional support for the assignment.

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Hydrophilic polymers containing chiral nucleic acid base pendants as polynucleotide analogs

Cited by 13 publications

References 11 publications

Hydrophilic polymers of ordered conformation-nucleic acid models

Hydrophilic polymers of ordered conformation-nucleic acid models

Polymerization of Cyclic Monomers Containing Phosphorus

Calorimetric studies of the polynucleotide analog poly(−)2‐[2‐(thymin‐1‐yl) propanamido]propenoic acid

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