- Influence of pendant chiral Cγ-(alkylideneamino/guanidino) cationic side-chains of PNA backbone on hybridization with complementary DNA/RNA and cell permeability
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Intrinsically cationic and chiral Cγ-substituted peptide nucleic acid (PNA) analogues have been synthesized in the form of γ(S)-ethyleneamino (eam)- and γ(S)-ethyleneguanidino (egd)-PNA with two carbon spacers from the backbone. The relative stabilization (ΔTm) of duplexes from modified cationic PNAs as compared to 2-aminoethylglycyl (aeg)-PNA is better with complementary DNA (PNA:DNA) than with complementary RNA (PNA:RNA). Inherently, PNA:RNA duplexes have higher stability than PNA:DNA duplexes, and the guanidino PNAs are superior to amino PNAs. The cationic PNAs were found to be specific toward their complementary DNA target as seen from their significantly lower binding with DNA having single base mismatch. The differential binding avidity of cationic PNAs was assessed by the displacement of DNA duplex intercalated ethidium bromide and gel electrophoresis. The live cell imaging of amino/guanidino PNAs demonstrated their ability to penetrate the cell membrane in 3T3 and MCF-7 cells, and cationic PNAs were found to be accumulated in the vicinity of the nuclear membrane in the cytoplasm. Fluorescence-activated cell sorter (FACS) analysis of cell permeability showed the efficiency to be dependent upon the nature of cationic functional group, with guanidino PNAs being better than the amino PNAs in both cell lines. The results are useful to design new biofunctional cationic PNA analogues that not only bind RNA better but also show improved cell permeability. (Graph Presented).
- Jain, Deepak R.,Anandi V, Libi,Lahiri, Mayurika,Ganesh, Krishna N.
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- Cγ(S/ R)-Bimodal Peptide Nucleic Acids (Cγ- bm-PNA) Form Coupled Double Duplexes by Synchronous Binding to Two Complementary DNA Strands
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Peptide nucleic acids (PNAs) are linear equivalents of DNA with a neutral acyclic polyamide backbone that has nucleobases attached via tert-amide link on repeating units of aminoethylglycine. They bind complementary DNA or RNA with sequence specificity to form hybrids that are more stable than the corresponding DNA/RNA self-duplexes. A new type of PNA termed bimodal PNA [Cγ(S/R)-bm-PNA] is designed to have a second nucleobase attached via amide spacer to a side chain at Cγon the repeating aeg units of PNA oligomer. Cγ-bimodal PNA oligomers that have two nucleobases per aeg unit are demonstrated to concurrently bind two different complementary DNAs, to form duplexes from both tert-amide side and Cγside. In such PNA:DNA ternary complexes, the two duplexes share a common PNA backbone. The ternary DNA 1:Cγ(S/R)-bm-PNA:DNA 2 complexes exhibit better thermal stability than the isolated duplexes, and the Cγ(S)-bm-PNA duplexes are more stable than Cγ(R)-bm-PNA duplexes. Bimodal PNAs are first examples of PNA analogues that can form DNA2:PNA:DNA1 double duplexes via recognition through natural bases. The conjoined duplexes of Cγ-bimodal PNAs can be used to generate novel higher-level assemblies.
- Bhingardeve, Pramod,Madhanagopal, Bharath Raj,Ganesh, Krishna N.
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p. 13680 - 13693
(2020/12/15)
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- METHODS FOR INHIBITING DRUG DEGRADATION
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Paragraph 0254; 0255
(2015/11/02)
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- HIV PROTEASE INHIBITOR AND CYTOCHROME P450 INHIBITOR COMBINATIONS
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Compositions and methods of treating viral infections are provided. More particularly, compositions including a combination of protease inhibitors and cytochrome p450 enzyme inhibitors are provided. Methods of using the compositions for treatment of disea
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Page/Page column 46
(2009/10/18)
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- COMPOSITIONS AND METHODS FOR INHIBITING CYTOCHROME P450
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Page/Page column 49
(2008/06/13)
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- PEPTIDOMIMETICS SELECTIVE FOR THE SOMATOSTATIN RECEPTOR SUBTYPES 1 AND/OR 4
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The invention relates to (hetero)arylsulfonylamino based peptidomimetics of formula (I), wherein A, D, E, J, Q1 R1 , R2, R3, p and j are defined as disclosed, or a pharmaceutically acceptable salt or ester thereof. Compounds of formula (I) possess high affinity and selectivity for the somatostatin receptor subtypes sst1 and/or sst4 and can be used for the treatment or diagnosis of diseases or conditions wherein sst1 and/or sst4 agonists or antagonists are indicated to be useful.
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Page/Page column 71
(2010/11/24)
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- Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase
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There are described according to the invention compounds of formula (I) (relative stereochemistry indicated), wherein R1, R2, R3 and X are as defined in the specification, together with processes for preparing them, compositions containing them and their use as pharmaceuticals. Compounds of formula (I) are indicated inter alia for the treatment of chronic bronchitis.
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