Chemical synthesis of illudalic acid analogs for stimulant use disorder

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PROJECT SUMMARY The objective of this undergraduate-centered project is to develop innovations in chemical synthesis that produce novel therapeutic lead compounds for stimulant use disorder. Stimulant use disorder affects millions of Americans. Overdose deaths involving stimulants have increased significantly in recent years, and they surged during the COVID-19 pandemic, especially in conjunction with opioid abuse. There are no FDA-approved medications for stimulant use disorder, but the protein tyrosine phosphatase receptor-type D (PTPRD) has been identified as an important therapeutic target. Genetic studies link higher PTPRD expression levels with greater propensity for substance abuse and addiction, and reducing PTPRD activity reduces cocaine-seeking behavior in mice. PTPRD inhibitors thus provide potential new avenues for developing treatments for stimulant use disorder. The natural product illudalic acid is a potent PTPRD inhibitor. Chemical synthesis of illudalic acid has been prohibitively difficult, so a simplified analog known as 7-BIA emerged as a lead compound for targeting PTPRD. 7-BIA was more synthetically accessible than illudalic acid but is less potent. Illudalic acid (and 7-BIA) is postulated to bind reversibly in the PTPRD catalytic domain, unmask a reactive dialdehyde, and then ligate covalently to a key cysteine residue, irreversibly blocking PTPRD activity. Synthesis of illudalic acid analogs is proposed. Preliminary results establish a convergent 5-step synthesis (longest linear sequence, LLS) of illudalic acid, whereas prior approaches require 16-20 linear steps. The key step here is a [4+2] benzannulation to assemble the fully substituted arene core and carbon framework. Undergraduate students will develop the approach and related methodology for the synthesis and late-stage functionalization of illudalic acid analogs, called “illudalogs”. Compounds will be evaluated for PTPRD inhibitory activity and selectivity, alongside illudalic acid and 7-BIA as positive controls. The rationale for this work is that illudalic acid-based PTPRD inhibitors can lead to pharmacotherapies for stimulant use disorder. Three complementary aims focus on: (1) developing the synthetic chemistry of the illudalogs, including late- stage functionalization and a new benzannulation; (2) building and maintaining a synthetic compound library of diverse illudalogs for structure-activity relationship (SAR) studies and lead identification; and (3) creating functional probes for PTPRD enzymology and cell biology. Expected outcomes include innovations in chemical synthesis that provide transformative access to PTPRD inhibitors and probes. These outcomes will support development of the therapeutic potential of PTPRD as a target for antiaddiction medication.