Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship
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 <i>N</i>1-ribosylated, Ca<sup>2+</sup>-mobilizing, second me...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/23/7165 |
| _version_ | 1797507372732645376 |
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| author | Joanna M. Watt Richard Graeff Barry V. L. Potter |
| author_facet | Joanna M. Watt Richard Graeff Barry V. L. Potter |
| author_sort | Joanna M. Watt |
| collection | DOAJ |
| description | 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 <i>N</i>1-ribosylated, Ca<sup>2+</sup>-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). <i>N</i>1-Inosine 5′-monophosphate (<i>N</i>1-IMP) is a fragment directly related to cADPR. 8-Substituted-<i>N</i>1-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 <i>N</i>1-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-NH<sub>2</sub>-<i>N</i>1-IMP is the most potent inhibitor (IC<sub>50</sub> = 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. |
| first_indexed | 2024-03-10T04:48:34Z |
| format | Article |
| id | doaj.art-a4b277117732405ca369cdbf4afde384 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T04:48:34Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a4b277117732405ca369cdbf4afde3842023-11-23T02:48:23ZengMDPI AGMolecules1420-30492021-11-012623716510.3390/molecules26237165Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity RelationshipJoanna M. Watt0Richard Graeff1Barry V. L. Potter2Medicinal Chemistry & Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Physiology, University of Hong Kong, Hong Kong, ChinaMedicinal Chemistry & Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKAlthough 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 <i>N</i>1-ribosylated, Ca<sup>2+</sup>-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). <i>N</i>1-Inosine 5′-monophosphate (<i>N</i>1-IMP) is a fragment directly related to cADPR. 8-Substituted-<i>N</i>1-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 <i>N</i>1-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-NH<sub>2</sub>-<i>N</i>1-IMP is the most potent inhibitor (IC<sub>50</sub> = 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.https://www.mdpi.com/1420-3049/26/23/7165synthesiscADPRcyclasenucleotidefragment |
| spellingShingle | Joanna M. Watt Richard Graeff Barry V. L. Potter Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship Molecules synthesis cADPR cyclase nucleotide fragment |
| title | Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship |
| title_full | Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship |
| title_fullStr | Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship |
| title_full_unstemmed | Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship |
| title_short | Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-<i>N</i>1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship |
| title_sort | small molecule cd38 inhibitors synthesis of 8 amino i n i 1 inosine 5 monophosphate analogues and early structure activity relationship |
| topic | synthesis cADPR cyclase nucleotide fragment |
| url | https://www.mdpi.com/1420-3049/26/23/7165 |
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