Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library

A library of eighty one adenosine antibiotic analogs was prepared under the Pilot Scale Library Program of the NIH Roadmap initiative from 5′-amino-5′-deoxy-2′,3′-<i>O</i>-isopropylidene-adenosine <b>3</b>. Diverse aldehyde, sulfonyl chloride and carboxylic acid reactant sets were condensed to <b>3</b>, in solution-phase fashion, leading after acid-mediated hydrolysis to the targeted compounds in good yields and high purity. No marked antituberculosis or anticancer activity was noted on preliminary cellular testing, but these nucleoside analogs should be useful candidates for other types of biological activity

Parallel Solution-Phase Synthesis and General Biological Activity of a Uridine Antibiotic Analog Library

A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine <b>2</b> and carboxylic acids <b>33</b> and <b>77</b> in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to <b>2</b>, leading after acid-mediated hydrolysis, to the targeted compounds <b>3</b>–<b>32</b> in good yields and high purity. Similarly, treatment of <b>33</b> with diverse amines and sulfonamides gave <b>34</b>–<b>75</b>. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of <b>33</b> followed by sodium hydroxide treatment led to carboxylic acid analog <b>77</b>. Hydrolysis of this material gave analog <b>78</b>. The intermediate <b>77</b> served as the precursor for the preparation of novel dipeptidyl uridine analogs <b>79</b>–<b>99</b> through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program

The D3 receptor antagonist SR 21502 reduces cue-induced reinstatement of methamphetamine-seeking in rats

There is as of yet no FDA-approved medication for methamphetamine use disorder. Although dopamine D3 receptor antagonists have been shown to be useful in reducing methamphetamine seeking in animal models their translation to the clinic has been hindered because currently tested compounds can produce dangerously high blood pressure. Thus, it is important to continue to explore other classes of D3 antagonists. We report here the effects of SR 21502, a selective D3 receptor antagonist, on cue-induced reinstatement (i.e., relapse) of methamphetamine-seeking in rats. In Experiment 1, rats were trained to self-administer methamphetamine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with one of several doses of SR 21502 on cue-induced reinstatement of responding. SR 21502 significantly reduced cue-induced reinstatement of methamphetamine-seeking. In Experiment 2, animals were trained to lever press for food under a PR schedule and tested with the lowest dose of SR 21502 that caused a significant reduction in Experiment 1. These animals responded on average 8 times more than the vehicle-treated rats in Experiment 1, eliminating the possibility that SR 21502-treated rats in Experiment 1 responded less because they were incapacitated. In summary, these data suggest that SR 21502 may selectively inhibit methamphetamine-seeking and may constitute a promising pharmacotherapeutic agent for methamphetamine or other drug use disorders.12 month embargo; first published 12 April 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter

Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [3H]DA uptake but preserved the Vmax of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [3H]Nisoxetine binding and reduced both [3H]DA and [3H]MPP+ efflux but did not affect d-amphetamine-mediated [3H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat1–86-induced decrease in [3H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat1–86–hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse

Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library

Disruptor of Telomeric Silencing 1-Like (DOT1L), the sole histone H3 lysine 79 (H3K79) methyltransferase, is required for leukemogenic transformation in a subset of leukemias bearing chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene, as well as other cancers. Thus, DOT1L is an attractive therapeutic target and discovery of small molecule inhibitors remain of high interest. Herein, we are presenting screening results for a unique focused library of 1200 nucleoside analogs originally produced under the aegis of the NIH Pilot Scale Library Program. The complete nucleoside set was screened virtually against DOT1L, resulting in 210 putative hits. In vitro screening of the virtual hits resulted in validation of 11 compounds as DOT1L inhibitors clustered into two distinct chemical classes, adenosine-based inhibitors and a new chemotype that lacks adenosine. Based on the developed DOT1L ligand binding model, a structure-based design strategy was applied and a second-generation of non-nucleoside DOT1L inhibitors was developed. Newly synthesized compound 25 was the most potent DOT1L inhibitor in the new series with an IC50 of 1.0 μM, showing 40-fold improvement in comparison with hit 9 and exhibiting reasonable on target effects in a DOT1L dependent murine cell line. These compounds represent novel chemical probes with a unique non-nucleoside scaffold that bind and compete with the SAM binding site of DOT1L, thus providing foundation for further medicinal chemistry efforts to develop more potent compounds. [Display omitted] •Virtual screening of unique 1200 nucleoside analogs library against DOT1L.•11 compounds were confirmed and clustered into two distinct chemical classes.•A series of non-nucleoside DOT1L inhibitors was developed by structure-based design.•25 with N-aminoethyl-pyrrolopyrimidin-4-amine scaffold has 40-fold improvement