We describe the synthesis of short double-stranded DNA fragments (see 4 and 13) which are capped on both ends by an optimally designed linker molecule. The new structures are stable with respect to hybrid dissociation and should have implications in physical studies involving double-stranded DNA as well as in the antisense area for the specific modulation of gene expressions.1. Introduction. -Physical studies on DNA and DNA complexes with proteins/peptides or small molecules are mainly performed on oligonucleotide duplexes in order to decrease complexity. A drawback with oligonucleotides is that they often show a dynamic behavior with respect to hybridization, oligomer formation, and stem loop structures. One way to overcome these limitations is by cross-linking the two single-stranded DNA fragments. This may be achieved oiu internal disulfide cross-links, but this approach might disturb the instrinsic properties of the oligonucleotide double strand [ 11. Another possible solution is cyclic DNA with a complementary region. However, this creates dumbbell-like structures with loop formation on both sides adjacent to the complementary region thus hampering optimal hybridization [2] [3] (Fig. l a ) . A recently described stabilization of duplex DNA makes use of a hairpin structure which is cross-linked at the end by a disulfide bridge [4].
We report a solid-phase synthesis of 3-acyltetramic acids that are components of naturally occurring antibiotics. The products were obtained in satisfactory purity by a novel cyclization-cleavage strategy via a Dieckmann condensation.Combinatorial chemistry started with the sequential synthesis of peptide libraries on solid support and is now being applied towards the synthesis of catalysts, polymers, drug-like molecules and very recently towards more complex natural products like epothilones. 1 The elaboration of combinatorial synthesis methods for various classes of interesting organic backbone structures as e.g. natural products represents a challenge for modern organic chemistry in the pharmaceutical industry. Whereas natural product chemistry has typically concentrated on the most efficient synthesis of one particular compound in the past, combinatorial chemistry aims rather at the simultaneous synthesis of structurally related compounds -compound libraries. Ideally, such new combinatorial synthetic procedures should be amenable towards parallel or split-mix automated robotics synthesis. We present here a facile, solid-phase synthesis that illustrates the above mentioned approach for the synthesis of 3-acyltetramic acids.3-Acyltetramic acids are substructures observed in several natural products that exhibit antibiotic activities. 2 A range of solution phase synthetic strategies have been reported. 2,3 A novel synthesis and purification method for tetramic acid derivatives has been published recently that takes advantage of the acidic nature of tetramic acids by using cationic ion exchanger resins to adsorb and release the final products selectively. 4 Our synthetic strategy is an extension of the published results and allows to generate combinatorial libraries of 3-acyltetramic acid derivatives using a solid phase support. The compounds are obtained in high purity and tedious purification of reaction intermediates or end products that may occur in several tautomeric forms and tend to form complexes or salts with metals and bases, respectively, is not necessary.The synthesis starts with Fmoc-protected amino acids that are linked via an ester bond to a high-loading hydroxymethyl polystyrene resin. After standard deprotection, the free amine 1 is reacted with aldehydes to give the corresponding azomethines 2. The progress of the reaction is easily monitored on beads by ATR-IR following the disappearance of free NH 2 groups. To achieve complete conversion for a broad range of aliphatic and aromatic aldehydes this condensation step had to be repeated. Subsequent acid catalyzed reduction with sodium cyanoborohydride in DMF gave the reductive alkylation products 3. This reduction step had to be carried out twice in order to achieve almost quantitative conversion as revealed by attenuated total reflection infrared spectroscopy of single resin beads (ATR-IR) by the disappearance of the C=N absorption at 1640 cm -1 . Attempts to perform the reductive N-alkylation in a single step using e.g. NaCNBH 3 , aldehyde and Mg...
A mechanical apparatus for the simultaneous synthesis of different DNA fragments on solid support is described. This new system allows the use of different kinds of supports and is amenable to automation. Utilizing this apparatus the synthesis of DNA fragments can be speeded up considerably. The effectiveness of the system is demonstrated by the simultaneous synthesis of DNA fragments up to 36 nucleotides long using phosphoamidites as building blocks and controlled pore glass as solid support.
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.