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  • Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Wang, W., Ranjan, A., Zhang, W., Liang, Q., MacMillan, K. S., Chapman, K., Wang, X., Chandrasekaran, P., Williams, N. S., Rosenbaum, D. M., De Brabander, J. K. 2024; 99: 129624


    A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX2R coupled Gq signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

    View details for DOI 10.1016/j.bmcl.2024.129624

    View details for Web of Science ID 001171642200001

    View details for PubMedID 38272190

  • Charge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism. Nature communications Li, Z., Amaya, L., Pi, R., Wang, S. K., Ranjan, A., Waymouth, R. M., Blish, C. A., Chang, H. Y., Wender, P. A. 2023; 14 (1): 6983


    The introduction of more effective and selective mRNA delivery systems is required for the advancement of many emerging biomedical technologies including the development of prophylactic and therapeutic vaccines, immunotherapies for cancer and strategies for genome editing. While polymers and oligomers have served as promising mRNA delivery systems, their efficacy in hard-to-transfect cells such as primary T lymphocytes is often limited as is their cell and organ tropism. To address these problems, considerable attention has been placed on structural screening of various lipid and cation components of mRNA delivery systems. Here, we disclose a class of charge-altering releasable transporters (CARTs) that differ from previous CARTs based on their beta-amido carbonate backbone (bAC) and side chain spacing. These bAC-CARTs exhibit enhanced mRNA transfection in primary T lymphocytes in vitro and enhanced protein expression in vivo with highly selective spleen tropism, supporting their broader therapeutic use as effective polyanionic delivery systems.

    View details for DOI 10.1038/s41467-023-42672-x

    View details for PubMedID 37914693

  • Evaluation of the efficacy of the hypocretin/orexin receptor agonists TAK-925 and ARN-776 in narcoleptic orexin/tTA; TetO-DTA mice. Journal of sleep research Sun, Y., Ranjan, A., Tisdale, R., Ma, S., Park, S., Haire, M., Heu, J., Morairty, S. R., Wang, X., Rosenbaum, D. M., Williams, N. S., De Brabander, J. K., Kilduff, T. S. 2023: e13839


    The sleep disorder narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor-2 (HCRTR2) agonists in narcoleptic male orexin/tTA; TetO-DTA mice. TAK-925 (1-10mg/kg, s.c.) and ARN-776 (1-10mg/kg, i.p.) were injected 15min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (Tsc ) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK-925 and ARN-776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK-925 and ARN-776 caused dose-related delays in NREM sleep onset. All doses of TAK-925 and all but the lowest dose of ARN-776 eliminated cataplexy during the first hour after treatment; the anti-cataplectic effect of TAK-925 persisted into the second hour for the highest dose. TAK-925 and ARN-776 also reduced the cumulative amount of cataplexy during the 6 h post-dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post-dosing. TAK-925 and ARN-776 also increased gross motor activity, running wheel activity, and Tsc , suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HCRTR2 agonists.

    View details for DOI 10.1111/jsr.13839

    View details for PubMedID 36808670

  • Secreted factors induced by PKC modulators do not indirectly cause HIV latency reversal. Virology Moran, J. A., Ranjan, A., Hourani, R., Kim, J. T., Wender, P. A., Zack, J. A., Marsden, M. D. 2023; 581: 8-14


    HIV can establish a long-lived latent infection in cells harboring integrated non-expressing proviruses. Latency reversing agents (LRAs), including protein kinase C (PKC) modulators, can induce expression of latent HIV, thereby reducing the latent reservoir in animal models. However, PKC modulators such as bryostatin-1 also cause cytokine upregulation in peripheral blood mononuclear cells (PBMCs), including cytokines that might independently reverse HIV latency. To determine whether cytokines induced by PKC modulators contribute to latency reversal, primary human PBMCs were treated with bryostatin-1 or the bryostatin analog SUW133, a superior LRA, and supernatant was collected. As anticipated, LRA-treated cell supernatant contained increased levels of cytokines compared to untreated cell supernatant. However, exposure of latently-infected cells with this supernatant did not result in latency reactivation. These results indicate that PKC modulators do not have significant indirect effects on HIV latency reversal in vitro and thus are targeted in their latency reversing ability.

    View details for DOI 10.1016/j.virol.2023.02.009

    View details for PubMedID 36842270

  • Trimethylene Methane Dianion Equivalent for the Asymmetric Consecutive Allylation of Aldehydes: Applications to Prins-Driven Macrocyclizations for the Synthesis of Bryostatin 1 and Analogues. The Journal of organic chemistry Wender, P. A., Luu-Nguyen, Q. H., Sloane, J. L., Ranjan, A. 2022


    We report a one-step (one-flask) generation and reaction of a bifunctional allylating reagent, a trimethylene methane dianion equivalent, that provides a route for the asymmetric 2-(trimethylsilylmethyl) allylation of aldehydes. The product of the first aldehyde allylation process is then set to engage in a second separate aldehyde allylation, providing an improved Prins macrocyclization strategy both for the scalable synthesis of bryostatin 1 and for the total synthesis of a new potent bryostatin analogue.

    View details for DOI 10.1021/acs.joc.2c02047

    View details for PubMedID 36378802