Efficient and Stereocontrolled Synthesis of 1,2,4-Trioxolanes Useful for Ferrous Iron-Dependent Drug Delivery

Fontaine, Shaun D.; DiPasquale, Antonio G.; Renslo, Adam R.

doi:10.1021/ol5028392

Cited by 26 publications

(31 citation statements)

References 26 publications

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“…A nonperoxidic dioxolane conjugate ( 3 ) was also prepared to confirm that the cytotoxicity of 1 is ablated in conjugated forms and that intracellular release of active 1 from 2 is peroxide-dependent (Figure 2a and Figure S2). Finally, trioxolane analog 4 (29) lacking the microtubule toxin was prepared to control for intrinsic cytotoxicity of the TRX moiety (Figure 2a). The cytotoxicity of the trioxolane-conjugate 2 and control compounds 1 , 3 , and 4 was then assessed across a small panel of cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…17,20 Given that labile Fe(II) promotes Fenton chemistry, we sought to develop a tumor-targeting strategy in which Fenton reaction of a peroxidic prodrug was coupled to release of drug payloads. Recognizing that antimalarial agents such as arterolane 21−24 exhibit finely tuned iron(II) reactivity, 25−28 we subsequently developed 29,30 an arterolane-inspired small molecule platform (denoted TRX herein) for Fe(II)-dependent drug delivery. These TRX-drug conjugates function via initial Fe(II)-promoted fragmentation of a 1,2,4-trioxolane ring to afford a cyclohexanone intermediate, followed by spontaneous β-elminiation and decarboxylation to release the drug payload (Figure 1 and Supporting Information Figure S1).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

et al. 2016

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Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

et al. 2016

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“…In ICL-1, we caged D-aminoluciferin with an Fe 2+ -reactive endoperoxide trigger (15,17,51) inspired by antimalarial agents that exhibit Fe 2+ -dependent pharmacology (52,53). ICL-1 was designed to undergo metal-and redox-specific Fe 2+ -dependent cleavage to generate D-aminoluciferin, which can interact with the firefly luciferase enzyme to produce red light output through a catalytic bioluminescent reaction.…”

Section: Significancementioning

confidence: 99%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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“…As we recently reported, trans-5 is available from 3-hydroxycyclohexanone in a three-step process involving a diastereoselective Griesbaum co-ozonolysis reaction as the key step. 16 While this same process can yield single enantiomers of 5 when starting from non-racemic 3-hydroxycyclohexanone, (±)-5 was employed for the studies reported herein. In a similar fashion, we prepared the conjugate 6 16 to explore the effects of 3"-carbamate substitution in a trioxolane analog more closely related to 2.…”

Section: Scheme 1 Trioxolane-mediated Release Of Mefloquine From Trimentioning

confidence: 99%

Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria

Lauterwasser¹,

Fontaine²,

et al. 2015

ACS Med. Chem. Lett.

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Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane-mefloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane-mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings.

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Efficient and Stereocontrolled Synthesis of 1,2,4-Trioxolanes Useful for Ferrous Iron-Dependent Drug Delivery

Cited by 26 publications

References 26 publications

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria

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