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Herein we report a DNA-compatible Biginelli reaction to construct isocytosine scaffolds. This reaction utilizes a one-pot reaction of DNA-conjugated guanidines with aldehydes and methyl cyanoacetates to give isocytosine derivatives, and the method is well compatible with different types of substrates. This is the first report on the synthesis of an isocytosine backbone in the field of DNA-compatible organic synthesis. The successful development of this reaction can widen the chemical space of DELs.
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http://dx.doi.org/10.1021/acs.orglett.3c01986 | DOI Listing |
RSC Med Chem
March 2025
Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia (P.O. 41522) Egypt
Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase.
View Article and Find Full Text PDFOrg Lett
July 2023
PharmaBlock Sciences (Nanjing), Inc., Nanjing 210032, Jiangsu Province, China.
Herein we report a DNA-compatible Biginelli reaction to construct isocytosine scaffolds. This reaction utilizes a one-pot reaction of DNA-conjugated guanidines with aldehydes and methyl cyanoacetates to give isocytosine derivatives, and the method is well compatible with different types of substrates. This is the first report on the synthesis of an isocytosine backbone in the field of DNA-compatible organic synthesis.
View Article and Find Full Text PDFChemistry
March 2015
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven (Belgium).
The synthesis, base-pairing properties and in vitro and in vivo characteristics of 5-methyl-isocytosine (isoC(Me) ) and isoguanine (isoG) nucleosides, incorporated in an HNA(h) (hexitol nucleic acid)-DNA(d) mosaic backbone, are described. The required h-isoG phosphoramidite was prepared by a selective deamination as a key step. As demonstrated by Tm measurements the hexitol sugar showed slightly better mismatch discrimination against dT.
View Article and Find Full Text PDFBioorg Med Chem Lett
December 2012
Discovery Informatics, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC(50) was obtained in the process. Five most potent compounds with nanomolar IC(50) values were selected for pharmacokinetics and in vivo experiments.
View Article and Find Full Text PDFBioorg Med Chem
May 2012
Discovery Informatics, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition.
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