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(α,α-dimethyl)glycyl (dmg) PNAs: achiral PNA analogs that form stronger hybrids with cDNA relative to isosequential RNA.

Gourishankar A, Ganesh KN - Artif DNA PNA XNA (2012 Jan-Mar)

Bottom Line: They show a higher binding to DNA relative to that with isosequential RNA.The results complement our previous work that had demonstrated that cyclohexanyl-PNAs favor binding with cRNA compared with cDNA and imply that the biophysical and structural properties of PNAs can be directed by introduction of the right rigidity in PNA backbone devoid of chirality.This approach of tweaking selectivity in binding of PNA constructs by installing gem-dimethyl substitution in PNA backbone can be extended to further fine-tuning by similar substitution in the aminoethyl segment as well either individually or in conjunction with present substitution.

View Article: PubMed Central - PubMed

Affiliation: Indian Institute of Science Education and Research, Division of Organic Chemistry, National Chemical Laboratory, Pune, India.

ABSTRACT
The design and facile synthesis of sterically constrained new analogs of PNA having gem-dimethyl substitutions on glycine (dmg-PNA-T) is presented. The PNA oligomers [aminoethyl dimethylglycyl (aedmg) and aminopropyl dimethylglycyl (apdmg)] synthesized from the monomers 6 and 12) effected remarkable stabilization of homothyminePNA(2):homoadenine DNA/RNA triplexes and mixed base sequence duplexes with target cDNA or RNA. They show a higher binding to DNA relative to that with isosequential RNA. This may be a structural consequence of the sterically rigid gem-dimethyl group, imposing a pre-organized conformation favorable for complex formation with cDNA. The results complement our previous work that had demonstrated that cyclohexanyl-PNAs favor binding with cRNA compared with cDNA and imply that the biophysical and structural properties of PNAs can be directed by introduction of the right rigidity in PNA backbone devoid of chirality. This approach of tweaking selectivity in binding of PNA constructs by installing gem-dimethyl substitution in PNA backbone can be extended to further fine-tuning by similar substitution in the aminoethyl segment as well either individually or in conjunction with present substitution.

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Figure 2. Structures of modified PNAs (A) aedmg, (B) apdmg, (C) apg and (D) spirocyclopentyl.
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Figure 2: Figure 2. Structures of modified PNAs (A) aedmg, (B) apdmg, (C) apg and (D) spirocyclopentyl.

Mentions: A simpler way to impart steric constrain without incorporating rigid and chiral cyclic moieties is to introduce gem-dialkyl substitution into the flexible aminoethylglycine backbone of PNA (Fig. 2A and B). Such acyclic, achiral backbone having gem-dialkyl function would not only be rigid, but if the steric constraints imposed lead to favorable pre-organization, the inherent binding to cDNA or RNA will be enhanced due to entropic factors. The gem-dimethyl substitution on glycine segment of PNA can be achieved by replacing the glycine in backbone with α-aminoisobutyric (aib) moiety to obtain the aminoethyl-(α,α-dimethyl)glycyl (aedmg) PNAs (Fig. 2A). A number of aib-containing peptides occur naturally and the gem-dimethyl substitution on α-carbon is well known to promote helices in polypeptides.23 This feature, although not directly extendible to PNA (which is not a classical peptide), provided an initial rationale for us to synthesize the gem-dimethyl substituted aedmg-PNA. To examine the correlated effects of steric constrain developed due to gem-dimethyl glycine on the backbone in the adjoining aminoethyl segment in backbone, PNA analogs having aminopropyl moiety [Fig. 2B, R = Me, aminopropyl-(α,α-dimethyl)glycyl (apdmg)-PNA)] were also synthesized for comparative studies of the DNA/RNA complementation abilities. The unsubstituted aminopropylglycine–PNA (Fig. 2C, apg-PNA) was reported to induce destabilization of the derived PNA:DNA hybrids.24 Synthesis of PNA with spirocyclopentyl substitution (Fig. 2D) on glycine is known in literature,25,26 but no data on its complementation properties are reported. It is demonstrated here that the incorporation of α,α-dimethyl substitution on glycine in PNA stabilizes the derived PNA:DNA and PNA:RNA hybrids with significant preference for the PNA:DNA binding.


(α,α-dimethyl)glycyl (dmg) PNAs: achiral PNA analogs that form stronger hybrids with cDNA relative to isosequential RNA.

Gourishankar A, Ganesh KN - Artif DNA PNA XNA (2012 Jan-Mar)

Figure 2. Structures of modified PNAs (A) aedmg, (B) apdmg, (C) apg and (D) spirocyclopentyl.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368815&req=5

Figure 2: Figure 2. Structures of modified PNAs (A) aedmg, (B) apdmg, (C) apg and (D) spirocyclopentyl.
Mentions: A simpler way to impart steric constrain without incorporating rigid and chiral cyclic moieties is to introduce gem-dialkyl substitution into the flexible aminoethylglycine backbone of PNA (Fig. 2A and B). Such acyclic, achiral backbone having gem-dialkyl function would not only be rigid, but if the steric constraints imposed lead to favorable pre-organization, the inherent binding to cDNA or RNA will be enhanced due to entropic factors. The gem-dimethyl substitution on glycine segment of PNA can be achieved by replacing the glycine in backbone with α-aminoisobutyric (aib) moiety to obtain the aminoethyl-(α,α-dimethyl)glycyl (aedmg) PNAs (Fig. 2A). A number of aib-containing peptides occur naturally and the gem-dimethyl substitution on α-carbon is well known to promote helices in polypeptides.23 This feature, although not directly extendible to PNA (which is not a classical peptide), provided an initial rationale for us to synthesize the gem-dimethyl substituted aedmg-PNA. To examine the correlated effects of steric constrain developed due to gem-dimethyl glycine on the backbone in the adjoining aminoethyl segment in backbone, PNA analogs having aminopropyl moiety [Fig. 2B, R = Me, aminopropyl-(α,α-dimethyl)glycyl (apdmg)-PNA)] were also synthesized for comparative studies of the DNA/RNA complementation abilities. The unsubstituted aminopropylglycine–PNA (Fig. 2C, apg-PNA) was reported to induce destabilization of the derived PNA:DNA hybrids.24 Synthesis of PNA with spirocyclopentyl substitution (Fig. 2D) on glycine is known in literature,25,26 but no data on its complementation properties are reported. It is demonstrated here that the incorporation of α,α-dimethyl substitution on glycine in PNA stabilizes the derived PNA:DNA and PNA:RNA hybrids with significant preference for the PNA:DNA binding.

Bottom Line: They show a higher binding to DNA relative to that with isosequential RNA.The results complement our previous work that had demonstrated that cyclohexanyl-PNAs favor binding with cRNA compared with cDNA and imply that the biophysical and structural properties of PNAs can be directed by introduction of the right rigidity in PNA backbone devoid of chirality.This approach of tweaking selectivity in binding of PNA constructs by installing gem-dimethyl substitution in PNA backbone can be extended to further fine-tuning by similar substitution in the aminoethyl segment as well either individually or in conjunction with present substitution.

View Article: PubMed Central - PubMed

Affiliation: Indian Institute of Science Education and Research, Division of Organic Chemistry, National Chemical Laboratory, Pune, India.

ABSTRACT
The design and facile synthesis of sterically constrained new analogs of PNA having gem-dimethyl substitutions on glycine (dmg-PNA-T) is presented. The PNA oligomers [aminoethyl dimethylglycyl (aedmg) and aminopropyl dimethylglycyl (apdmg)] synthesized from the monomers 6 and 12) effected remarkable stabilization of homothyminePNA(2):homoadenine DNA/RNA triplexes and mixed base sequence duplexes with target cDNA or RNA. They show a higher binding to DNA relative to that with isosequential RNA. This may be a structural consequence of the sterically rigid gem-dimethyl group, imposing a pre-organized conformation favorable for complex formation with cDNA. The results complement our previous work that had demonstrated that cyclohexanyl-PNAs favor binding with cRNA compared with cDNA and imply that the biophysical and structural properties of PNAs can be directed by introduction of the right rigidity in PNA backbone devoid of chirality. This approach of tweaking selectivity in binding of PNA constructs by installing gem-dimethyl substitution in PNA backbone can be extended to further fine-tuning by similar substitution in the aminoethyl segment as well either individually or in conjunction with present substitution.

Show MeSH
Related in: MedlinePlus