Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-N1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship
| Autor: | Richard M. Graeff, Joanna M. Watt, Barry V. L. Potter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
synthesis
Stereochemistry Pharmaceutical Science Organic chemistry 010402 general chemistry 01 natural sciences Cyclase fragment Analytical Chemistry 03 medical and health sciences chemistry.chemical_compound QD241-441 Drug Discovery medicine Structure–activity relationship Physical and Theoretical Chemistry Inosine 030304 developmental biology cADPR cyclase nucleotide 0303 health sciences Total synthesis Ligand (biochemistry) Adenosine Small molecule 0104 chemical sciences chemistry Chemistry (miscellaneous) Molecular Medicine Bioisostere medicine.drug |
| Zdroj: | Molecules; Volume 26; Issue 23; Pages: 7165 Watt, J M, Graeff, R & Potter, B V L 2021, ' Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-N1-Inosine 5'-Monophosphate, Analogues and Early Structure-Activity Relationship ', Molecules, vol. 26, no. 23, 7165 . https://doi.org/10.3390/molecules26237165 Molecules, Vol 26, Iss 7165, p 7165 (2021) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules26237165 |
| Popis: | Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the N1-ribosylated, Ca2+-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). N1-Inosine 5′-monophosphate (N1-IMP) is a fragment directly related to cADPR. 8-Substituted-N1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the N1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5′-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH2-N1-IMP is the most potent inhibitor (IC50 = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach. |
| Databáze: | OpenAIRE |
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