Gerhard Breipohl

PNA: Synthetic Polyamide Nucleic Acids with Unusual Binding Properties

The astonishing discovery that peptide nucleic acids (PNAs, B=nucleobase), in spite of their drastic structural difference to natural DNA, are better nucleic acid mimetics than many other oligonucleotides has resulted in an explosion of research into this class of compounds. The synthesis, physical properties, and biological interactions of PNAs as well as their chimeras with DNA and RNA are summarized here.

Reduction of infarct size by local angiotensin-converting enzyme inhibition is abolished by a bradykinin antagonist.

We investigated the role of local (cardiac) bradykinin in the infarct-limiting effect of the ACE inhibitor, ramiprilat, by using the novel bradykinin antagonist, HOE 140

Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin)

HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a new B2 antagonist, was compared to R-493 (D-Arg[Hyp3-D-Phe7,Leu8]bradykinin) with respect to inhibition of the responses of seven isolated smooth muscle preparations to bradykinin. R-493 was found to exert: (a) high antagonistic activity on the rabbit jugular vein (pA2 of 8.86), (b) moderate activity on the rabbit aorta, guinea-pig ileum, hamster urinary bladder and human urinary bladder (pA2 of 5.76, 6.77, 7.16 and 7.15, respectively) and (c) a stimulatory effect on the guinea-pig trachea. On the other hand, HOE 140 showed identical apparent affinities (8.36-9.12) on all preparations except the rabbit aorta where it was inactive and the guinea-pig trachea where the compound was an antagonist (pA2: 7.42) without agonistic effect. HOE 140 is specific and selective for B2 receptors since it was inactive against angiotensin II, substance P, neurokinin A, desArg9-bradykinin, noradrenaline or acetylcholine in the various preparations. R-493 inhibited the contractile effects of bradykinin competitively, while HOE 140 was not competitive even at low concentrations (7.7 x 10(-9) M). These results demonstrate that HOE 140 is a potent B2 antagonist with high affinity, specific for kinin receptors and selective for the B2 receptor type, but is non-competitive. HOE 140 is the first bradykinin receptor antagonist that acts as such on the guinea-pig trachea without showing any agonistic activity.

The synthesis of polyamide nucleic acids using a novel monomethoxytrityl protecting-group strategy

Abstract The preparation of novel monomethoxytrityl (Mmt) protected monomers for the synthesis of polyamide nucleic acids (PNAs) is described. The use of base-labile acyl-type nucleobase protecting groups and of a succinyl-linked solid-support offers a synthetic strategy similar to standard oligonucleotide synthesis conditions. This strategy has been successfully applied for the synthesis of PNAs of mixed base sequence.

DesArg9D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (desArg10-[Hoe140]) is a bradykinin B1 receptor antagonist

Abstract DesArg 9 -D-Arg[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]BK is a potent and stable B 1 bradykinin (BK) receptor antagonist which was one order of magnitude more potent (IC 50 1.2 × 10 −8 M) in the isolated rabbit aorta than the known selective B 1 BK receptor antagonist, desArg 9 -[Leu 8 ]BK (IC 50 1.1 × 10 −7 M). DesArg 9 -D-Arg[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]BK is the desArg 10 derivative of Hoe 140, a new, potent, stable, selective and long-acting B 2 BK receptor antagonist. In B 2 organ preparation it was three orders of magnitude less potent than Hoe140. Since it is potent and stable it could contribute to the investigation of B 1 BK receptor function.

Novel synthetic routes to PNA monomers and PNA-DNA linker molecules

Abstract Novel methods for the preparation of monomethoxytrityl (Mmt) protected aminoethylglycine building blocks and dimethoxytrityl (Dmt) protected hydroxyethylglycine derivatives useful for the synthesis of polyamide nucleic acids (PNAs) and PNA/DNA chimeras are described. The protecting group strategy employed for PNA monomer synthesis produces easily isolable intermediates, minimizes chromatographic purification, and is suitable for large-scale monomer synthesis.

PNAs: synthetische Polyamidnucleinsäuren mit außergewöhnlichen Bindungseigenschaften

Auserst uberraschend war die Erkenntnis, das Peptidnucleinsauren (PNAs, B=Nucleobase) trotz ihrer drastisch vom naturlichen DNA-Ruckgrat abweichenden Struktur besser als die meisten Oligonucleotidderivate als Nucleinsauremimetica genutzt werden konnen. Die Synthese, physikalischen Eigenschaften und biologischen Wechselwirkungen sowohl der PNAs als auch ihrer Chimaren mit DNA und RNA werden hier zusammenfassend beschrieben.

Synthesis of polyamide nucleic acids (PNAs) using a novel Fmoc/Mmt protecting-group combination

Abstract The preparation of 9-Fluorenylmethoxycarbonyl(Fmoc) protected building blocks for the synthesis of polyamide nucleic acids (PNAs) is described. Use of 4-Methoxyphenyldiphenylmethyl (Mmt)-protecting groups for the exocyclic amino function of the nucleobases enhances the solubility of the monomers and allows final deprotection by mild acid treatment. The novel synthetic route is exemplified by the synthesis of heptameric and octameric PNAs.

RGD Mimetics containing a central hydantoin scaffold: αVβ3 vs αIIbβ3 selectivity requirements

Abstract The synthesis of a series of RGD mimetic α V β 3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective α V β 3 antagonists (vs α IIb β 3 ) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.

αvβ3 Antagonists Based on a Central Thiophene Scaffold

Abstract A series of novel, highly potent αvβ3 antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and β-amino acids were explored with respect to inhibition of αvβ3 mediated cell adhesion and selectivity versus αIIbβ3 binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.