Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Wang, Xiaofang; Creek, Darren J.; Schiaffo, Charles E.; Dong, Yuxiang; Chollet, Jacques; Scheurer, Christian; Wittlin, Sergio; Charman, Susan A.; Dussault, Patrick H.; Wood, James K.; Vennerstrom, Jonathan L.

doi:10.1016/j.bmcl.2009.07.013

Cited by 31 publications

(25 citation statements)

References 28 publications

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“…Their activities are comparable to artesunate and artemether, both in vivo and in vitro, with improved pharmacokinetic (oral bioavailability, half-life, etc.) properties 24,32,33. The structures of some potent 2-adamantyl derivatives of trioxolane are given in Figure 8.…”

Section: Endoperoxide Antimalarials: Structural Diversity and Bioactimentioning

confidence: 99%

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Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

Rudrapal¹,

Chetia²

2016

DDDT

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Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains of Plasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistant P. falciparum malaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system lacking the lactone ring that constitutes the most important endoperoxide structural scaffold is believed to be the key pharmacophoric moiety and is primarily responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. Due to this reason, research into endoperoxide, particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based scaffolds, has gained significant interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive effort has been made to review the development of endoperoxide antimalarials from traditional antimalarial leads (natural/semisynthetic) and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based structural scaffolds, including their chimeric (hybrid) molecules, which are newer and potent antimalarial agents.

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Section: Endoperoxide Antimalarials: Structural Diversity and Bioactimentioning

confidence: 99%

“…It is believed that sometimes, these radical species directly target heme and alkylate heme molecule (parasite proteins). This alkylation mechanism is another key target of endoperoxide-based antimalarial drugs 32,64–69…”

Section: Pharmacodynamics Of Endoperoxide Antimalarialsmentioning

confidence: 99%

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

Rudrapal¹,

Chetia²

2016

DDDT

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“…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%

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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“…Arterolane (OZ277) (30) developed by J. L. Ve nnerstrom at the University of Nebraska, USA is today's most promising fully synthetic drug candidate against malaria. [13] It is also a demonstration of the detours research can make. Ozonides (1,2,4-trioxolanes) [14] were used by chemists as synthetic intermediates for more than 100 years, i.e.…”

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confidence: 97%

From Carbenes to Peroxidic Antimalarial Drugs. Highlights from the Scientific Work of Charles William Jefford

Bürger¹

2009

Chimia

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Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Abstract: -trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity" (2009). Patrick Dussault Publications. 8.

Cited by 31 publications

References 28 publications

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

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

From Carbenes to Peroxidic Antimalarial Drugs. Highlights from the Scientific Work of Charles William Jefford

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