Electrolytic Macrocyclizations: Scalable Synthesis of a Diazonamide‐Based Drug Development Candidate

Ding, Hui; DeRoy, Patrick; Perreault, Christian; Larivée, Alexandre; Siddiqui, A. M.; Caldwell, Charles G.; Harran, Susan; Harran, Patrick G.

doi:10.1002/anie.201411663

Cited by 128 publications

(62 citation statements)

References 40 publications

(18 reference statements)

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“…Here, we present DZ-2384, an optimized synthetic derivative of AB-5, which is in preclinical development. Relative to earlier diazonamide analogs, its synthesis is simplified and commercially scalable (21). DZ-2384 shows potent antitumor activity in multiple cancer models but causes negligible side effects (including neuropathy) at effective plasma concentrations.…”

Section: Introductionmentioning

confidence: 99%

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity

et al. 2016

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Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.

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Section: Introductionmentioning

confidence: 99%

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity

et al. 2016

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“…[163] One remarkable example,n amely the anodic intramolecular macrocyclization of aphenol and an indole moiety, was reported by Harran and co-workers. [164] Them ultistep synthesis of adiazonamide-based drug (DZ-2384;Scheme 58) involves macrocyclization by intramolecular C À Oa nd C À C bond formation. Thes electivity of the oxidative cyclization was increased and the reagent waste was minimized by development of an electrochemical protocol.…”

Section: Synthesis By Electrochemically Initiated Cyclizationmentioning

confidence: 99%

“…Electrochemical synthesis of the precursor for DZ-2384 on multigram scale by anodic macrocyclization. [164] Scheme 59. Synthesis of (+ +)-N-methylanisomycin by anodic cyclization of a d-alkenylamine.…”

Section: Synthesis By Electrochemically Initiated Cyclizationmentioning

confidence: 99%

Elektrifizierung der organischen Synthese

et al. 2018

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Die direkte Nutzung von Elektrizität für die organische Synthese erlebt derzeit eine Renaissance. Von den eher syntheseorientierten Laboratorien, die auf diesem Gebiet arbeiten, werden neuartige oder althergebrachte Konzepte genutzt, um den Weg von der Nischentechnologie zu breiteren Anwendungen zu ebnen. Da nur Elektronen als Reagens genutzt werden, wird die Bildung von Abfallreagentien effizient vermieden. Darüber hinaus können stöchiometrische Reagentien regeneriert werden und ermöglichen eine elektrokatalysierte Umsetzung. Die Anwendung von elektroorganischen Transformationen ist jedoch mehr als nur die Minimierung des Abfallaufkommens; sie führt vielmehr zu inhärent sicheren Prozessen, zur Abkürzung vieler Synthesestufen, zu milderen Reaktionsbedingungen, zu alternativen Zugängen zu gewünschten Struktureinheiten sowie zur Schaffung neuer Bereiche für geistiges Eigentum (Patente). Wenn die verwendete Elektrizität aus regenerativen Ressourcen stammt, kann dieser Stromüberschuss direkt als terminales Oxidations‐ oder Reduktionsmittel eingesetzt werden, was eine äußerst nachhaltige und damit hochattraktive Technologie darstellt. Dieser Aufsatz gibt einen Überblick über die jüngsten Entwicklungen auf dem Gebiet der elektrochemischen Synthese, welche die Zukunft dieses stark aufstrebenden Gebietes beeinflussen werden.

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“…The story of the novel antitubulin marine compound diazonamide and the problems associated with determining its correct structure were well described in papers from 1991 to 2001, and the multiple total syntheses have also been well documented as can be seen in references 1 to 5 in the 2015 paper by Ding et al describing the synthesis of DZ-2384 (Figure 5; 27 ) [64]. …”

Section: A Potential Warhead Compoundmentioning

confidence: 99%

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

Newman¹,

Cragg²

2017

Marine Drugs

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In this review, we have attempted to describe all of the antibody–drug conjugates using a marine-derived compound as the “warhead”, that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future.

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Electrolytic Macrocyclizations: Scalable Synthesis of a Diazonamide‐Based Drug Development Candidate

Cited by 128 publications

References 40 publications

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity

Elektrifizierung der organischen Synthese

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

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