Amidinourea lead compound and synthesis method thereof
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A lead compound and amidinourea technology, applied in the field of amidinourea lead compounds and their synthesis, can solve the problems of denaturation, DNA instability and the like, and achieve the effect of good application prospects
Pending Publication Date: 2022-05-13
康龙化成(宁波)科技发展有限公司 +1
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Problems solved by technology
However, due to the limitations of DNA chemistry, there are no reports on the reaction methodology for the synthesis of guaninourea compounds on DNA and the construction of gene-encoded compound libraries of guaninourea compounds.
[0010] Because the construction of DNA-encoded compound libraries depends on the stability of DNA, DNA must be stable in a certain aqueous phase, pH, temperature, metal ion concentration and inorganic salt concentration (Gironda-Martínez A.; Donckele E.J.; Samain F. et al. DNA-Encoded Chemical Libraries: A Comprehensive Review with Successful Stories and Future Challenges; ACS Pharmacol. Transl. Sci. 2021, 4, 4, 1265–1279.), heat, extreme pH or some organic reagents (such as Methanol, ethanol, urea, formamide, etc.) can easily cause DNA denaturation, resulting in DNA instability, and the reaction applied to the construction of a DNA-encoded compound library needs to have a high yield before it can be applied to a gene-encoded library
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Embodiment 1
[0117] Embodiment 1, the synthesis of oligomeric nucleic acid-guanidine compound raw material
[0118]
[0119] The oligonucleotide used in the present invention-NH 2 (DNA-NH 2 ) is composed of oligonucleotide (structure as follows, supplier GenScript, molecular weight 4937) with DMT-MM-BF 4 (supplier: Suzhou Capwell Pharmaceutical Technology Co., Ltd.) obtained by condensation of condensing agent and Fmoc-NH-PEG4-propionic acid (supplier: Bi De) by conventional methods (Li Y., Gabriele E., Samain F., Favalli N., Sladojevich F., Scheuermann., Optimized Reaction Conditions for Amide Bond Formation in DNA Encoded Combinatorial Libraries, Neri D. ACS Comb. Sci. 2016, 18, 8, 438–443.).
[0120]
[0121] Oligonucleotide (molecular weight 4937)
[0122] The synthetic method of oligomeric nucleic acid-guanidine compound raw material of the present invention comprises the steps:
[0123] 100nmol oligo-NH 2Dissolve it in deionized water to prepare an aqueous solution with a ...
Embodiment 2
[0126] Embodiment 2, the general synthetic method of oligomeric nucleic acid-guanidinourea compound
[0127] The synthetic reaction formula of universal oligomeric nucleic acid-guaninourea compound is as follows:
[0128]
[0129] In 0.5nmol oligonucleotide-guanidine compound aqueous solution (aqueous solution with a concentration of 1mmol / L, 1 equivalent, 0.5nmol, 0.5μL), add a sodium tetraborate buffer solution (1.0μL, pH=12.5) with a concentration of 250mmol / L and Isocyanate acetonitrile solution (isocyanate concentration is 1mol / L, 1000 equivalents, 500nmol, 0.5μL), react at 90°C, and add 500nmol isocyanate acetonitrile solution every 3 hours during the reaction (isocyanate concentration is 1mol / L, 1000 equivalents , 500nmol, 0.5μL), supplemented twice, a total of 1500nmol of isocyanate, a total of 22 hours of reaction. After the reaction was completed, a 10% total volume of 5 mol / L sodium chloride aqueous solution was added to the reaction liquid. Then, continue to a...
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Abstract
The invention provides an amidinourea lead compound and a synthesis method thereof, and belongs to the field of chemical synthesis. The amidinourea lead compound disclosed by the invention is shown as a formula I in the specification. According to the synthesis method of the amidinourea lead compound, a compound shown in a formula II and a compound shown in a formula III serve as raw materials and react in a solvent, and a compound shown in a formula I is obtained. The method for synthesizing the amidinourea lead compound on the DNA is disclosed for the first time, the damage to the DNA is small, and the integrity of the DNA is good in the reaction process; meanwhile, the method disclosed by the invention is good in universality and simple to operate, and the oligomeric nucleic acid-amidinourea compound can be prepared at high yield. According to the invention, the types of chemical reactions for synthesizing a coding compound library on DNA are enriched, a new amidinourea skeleton is constructed for synthesizing the DNA coding compound library, and the application prospect in the development of lead drugs is very good.
Description
technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a lead compound of guanyl urea and a synthesis method thereof. Background technique [0002] The development of any drug is a long and costly process. According to the known statistics of drug research and development, it takes an average of 10 years for a new drug to be put on the market from the beginning of research and development to its final approval, and the research cost is as high as 2.5 billion US dollars (Holenz J.; Stoy P. Advances in lead generation[J] ]. Bioorg. Med. Chem. Lett. 2019, 29, 517-524.). One of the important reasons why the drug development process is so long and expensive is that the discovery and optimization process of lead compounds is difficult and progress is slow (Brown D.G.; Jonas B. Where do recent small molecule clinical development candidates come from? [J]. J. Med. Chem., 2018, 61(21), 9442-9468.). In the process of research a...
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