143526-94-7Relevant academic research and scientific papers
Synthesis and evaluation of squaramide and thiosquaramide inhibitors of the DNA repair enzyme SNM1A
Berney, Mark,Doherty, William,Jauslin, Werner Theodor,McGouran, Joanna Francelle,T Manoj, Manav,Dürr, Eva-Maria
supporting information, (2021/09/06)
SNM1A is a zinc-dependent nuclease involved in the removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored. Herein, the synthesis of a family of squaramide- and thiosquaramide-bearing nucleoside derivatives and their evaluation as SNM1A inhibitors is reported. A gel electrophoresis assay was used to identify nucleoside derivatives bearing an N-hydroxysquaramide or squaric acid moiety at the 3′-position, and a thymidine derivative bearing a 5′-thiosquaramide, as candidate SNM1A inhibitors. Quantitative IC50 determination showed that a thymidine derivative bearing a 5′-thiosquaramide was the most potent inhibitor, followed by a thymidine derivative bearing a 3′-squaric acid. UV–Vis titrations were carried out to evaluate the binding of the (thio)squaramides to zinc ions, allowing the order of inhibitory potency to be rationalised. The membrane permeability of the active inhibitors was investigated, with several compounds showing promise for future in vivo applications.
Probing the binding requirements of modified nucleosides with the dna nuclease snm1a
Dürr, Eva-Maria,McGouran, Joanna F.
, (2021/06/21)
SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.
Dideoxyribonucleoside phosphamide monomer containing succinamide structure and synthesis method and application of dideoxyribonucleoside phosphamide monomer
-
Paragraph 0053-0057, (2020/06/20)
The invention provides a dideoxyribonucleoside phosphamide monomer containing a succinamide structure, its synthesis method and application, and belongs to the technical field of organic synthesis. Zidovudine is adopted as a raw material, and reactions of etherification, amidation, reduction and esterification are performed so as to prepare the dideoxyribonucleoside phosphamide monomer containinga succinamide structure. The dideoxyribonucleoside phosphamide monomer containing a succinamide structure has simple and clear synthesis steps, the operation is convenient, and the purification mode of intermediates and products is simple, so that a large number of the target product is prepared efficiently, and a structural modifier and synthesis method with controllable cost and simplicity andefficiency are provided for structural modification of nucleic acids.
Investigation of the effect of amino acid chirality in the internucleoside linker on DNA:DNA and DNA:RNA duplex stability
Bagmare, Seema,Gunjal, Anita D.,Kumar, Vaijayanti A.
, p. 2442 - 2449 (2015/03/30)
Abstract Enzymatically and chemically stable amide-linked di/oligonucleosides are highly desired synthetic targets in which the phosphodiester linkages in native DNA are replaced by amide linkers of appropriate length and stereochemistry. The five-atom am
Probing binding preferences of DNA and RNA: Backbone chirality of thioacetamido-linked nucleic acids and iso-thioacetamido-linked nucleic acids to differentiate DNA versus RNA selective binding
Gokhale, Sachin S.,Gogoi, Khirud,Kumar, Vaijayanti A.
scheme or table, p. 7431 - 7434 (2011/02/21)
Subtle differences in RNA and DNA duplex geometry could be sensed by the changed stereochemistry at 3′-amino function in the 5-atom thioacetamido linker of thioacetamido-linked nucleic acids and iso-thioacetamido-linked nucleic acids modified oligomers. I
Synthesis, structure-activity relationship and antiviral activity of 3′-N,N-dimethylamino-2′,3′-dideoxythymidine and its prodrugs
Singh, Ramendra K.,Yadav, Dipti,Rai, Diwakar,Kumari, Garima,Pannecouque,De Clercq, Erik
experimental part, p. 3787 - 3793 (2010/09/15)
A probable NRTI molecule, viz. 3′-N,N-dimethylamino-2′, 3′-dideoxythymidine (4) and its 5′-O-carboxyl ester prodrugs - 5′-(N-α-BOC-l-phenylalanyl)-3′-N,N-dimethylamino-2′, 3′-dideoxythymidine (5), 5′-l-phenylalanyl-3′-N,N- dimethylamino-2′,3′-dideoxythymidine (6) and 5′-decanoyl- 3′-N,N-dimethylamino-2′,3′-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity with EC50 value 0.03 μM (SI = 8) against VSV in Hela and HEL cell lines. However, the lead compound 4 and its derivatives 5, 6 and 7 showed no remarkable activity against HIV-1 and other viruses. Molecular docking studies with HIV-1 RT using DS 2.5 and pymol softwares have shown marked differences in the interaction patterns between the lead compound 4 and AZT. Synthesis, molecular modeling and antiviral/anti-HIV activity of 3′-N,N-dimethylamino-2′,3′-dideoxythymidine and its prodrugs have been described.
Convenient syntheses of 3′-amino-2′,3′- dideoxynucleosides, their 5′-monophosphates, and 3′-aminoterminal oligodeoxynucleotide primers
Eisenhuth, Ralf,Richert, Clemens
supporting information; experimental part, p. 26 - 37 (2009/04/07)
(Chemical Equation Presented) 5′-Protected 3′-amino-2′, 3′-dideoxynucleosides containing any of the four canonical nucleobases (A/C/G/T) were prepared via azides in five to six steps, starting from deoxynucleosides. For pyrimidines, the synthetic route in
Synthesis and RNA binding selectivity of oligonucleotides modified with five-atom thioacetamido nucleic acid backbone structures
Gogoi, Khirud,Gunjal, Anita D.,Phalgune, Usha D.,Kumar, Vaijayanti A.
, p. 2697 - 2700 (2008/02/09)
Equation Presented Convenient chemical synthesis and incorporation of dithymidine and thymidine-cytidine dimer blocks connected with a five-atom amide linker N3′-CO-CH2-S-CH2 into oligonucleotides (ONs) are reported. The UV-Tm/
Technetium-99m-labeling and synthesis of thymidine analogs: Potential candidates for tumor imaging
Teng, Bao,Bai, Yunpeng,Chang, Yu,Chen, Shizhen,Li, Zhaolong
, p. 3440 - 3444 (2008/02/10)
The technetium-99m-labeling and synthesis of a series of thymidine analogs were studied. The target molecules were obtained by using 6-hydrazinopyridine-3-carboxylic acid (HYNIC) as a bifunctional coupling agent and using N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) and ethylenediamine-N,N′-diacetic acid (EDDA) as coligands. The effects of different spacers between thymidine analog with HYNIC on radiochemical yield were also studied.
An efficient synthesis of 3′-amino-3′-deoxythymidine derivatives
Seregin,Chudinov,Yurkevich,Shvets
, p. 135 - 138 (2007/10/03)
An efficient method of reduction of 3′-azido-3′-deoxythymidine and its 5′-protected derivatives to 3′-aminothymidine derivatives on a palladium catalyst using ammonium formate as a source of hydrogen was suggested.
