Structure of Malaria Pigment and Related Propanoate‐Linked Metalloporphyrin Dimers

Bohle, D. Scott; Dodd, Erin L.; Stephens, Peter W.

doi:10.1002/cbdv.201200033

Cited by 31 publications

(34 citation statements)

References 49 publications

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“…Deuterohematin anhydride, DHA, the deuteroporphyrin devinylated analogue of HA, has been prepared by dehydrohalogenation of deuterohemin, DH, with the non‐coordinating base 2,6‐lutidine [Eq. (1)] . Solvent effects are important in these transformations, with other solvents and bases leading to different semicrystalline materials (Figure S6, Supporting Information) .…”

Section: Resultsmentioning

confidence: 99%

“…Vibrational spectroscopy remains one of the best tools for deciphering propionic acid interactions in the heme family of condensed phases and the structure of DHA provides a valuable new reference point for this technique. As shown in Figure , the IR spectrum of DHA features strong propionic acid side‐chain bands at

\overset{ν}{true}

=1729, 1654, 1587, and 1206 cm −1 .…”

Section: Resultsmentioning

confidence: 99%

“…(1)]. [15] Solvente ffects are importanti nt hese transformations, with other solvents and bases leading to different semicrystalline materials ( Figure S6, Supporting Information). [24] Thes tructure of the product recovered from DMSO/ MeOH was solved as ah ydrate from synchrotron powder diffraction data (Figures 2a nd 3; Figure S3), with Figure S2 showing the diffraction pattern and refinedf inal Rietveld fit.…”

Section: Resultsmentioning

confidence: 99%

“…[12] Ap articularlyc hallenging problem in the biosynthesis of HZ is its remarkable crystallinity and the rate at which as ingle phase crystallizes from the heterogeneous milieu of the digestive vacuole. [14] Following its original structurale lucidation by X-ray powder diffraction analysis in 2000, [13] there have been four separate powder diffraction structure determinations [15][16][17] as well as single-crystal structure determinations of aD MSOsolvated phase. [18] In each case, whether synthetic (hematin anhydride, HA 1 ) [13,15,16,18,19] or natural( HZ), [17] the structure consists of iron(III)(protoporphyrinato) dimers.…”

Section: Introductionmentioning

confidence: 99%

“…[14] Following its original structurale lucidation by X-ray powder diffraction analysis in 2000, [13] there have been four separate powder diffraction structure determinations [15][16][17] as well as single-crystal structure determinations of aD MSOsolvated phase. [18] In each case, whether synthetic (hematin anhydride, HA 1 ) [13,15,16,18,19] or natural( HZ), [17] the structure consists of iron(III)(protoporphyrinato) dimers. The reported variations in structural models are solely related to the presence/absence of solventm olecules interrupting the H-bonded propionic acid chain andd iffering modelso ft he vinyl disorder.T hus, regardless of source, natural or synthetic, HA and HZ are isostructural and have the base structure shown in Figure 1, ac hain of propionate-linked dimers.…”

Section: Introductionmentioning

confidence: 99%

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Hydrating the Bispropionate Notch in Malaria Pigment: A New Structural Motif in the Iron(III)(deuteroporphyrin) Dimer

Kuter

Suárez

Dodd

et al. 2019

Chemistry A European J

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Treating deuterohemin, chloro(deuteroporphyrinato)iron(III), with a non‐coordinating base in DMSO/methanol allows for the isolation of [(deuteroporphyrinato)iron(III)]2, deuterohematin anhydride (DHA), an analogue of malaria pigment, the natural product of heme detoxification by malaria. The structure of DHA obtained from this solvent system has been solved by X‐ray powder diffraction analysis and displays many similarities, yet important structural differences, to malaria pigment. Most notably, a water molecule of solvation occupies a notch created by the propionate side chains and stabilizes a markedly bent propionate ligand coordinated with a long Fe−O bond, and a carboxylate cluster associated with water molecules is generated. Together, these features account for its increased solubility and more open structure, with an increased porphyrin–porphyrin separation. The IR spectroscopic signature associated with this structure also accounts for the strong IR band at 1587 cm−1 seen for many amorphous preparations of synthetic malaria pigment, and it is proposed that stabilizing these structures may be a new objective for antimalarial drugs. The important role of the vinyl substituents in this biochemistry is further demonstrated by the structure of deuterohemin obtained by single‐crystal X‐ray diffraction analysis.

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Section: Resultsmentioning

confidence: 99%

\overset{ν}{true}

=1729, 1654, 1587, and 1206 cm −1 .…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hydrating the Bispropionate Notch in Malaria Pigment: A New Structural Motif in the Iron(III)(deuteroporphyrin) Dimer

Kuter

Suárez

Dodd

et al. 2019

Chemistry A European J

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The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction

et al. 2020

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The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α‐aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and ‐resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple‐negative breast cancer cell line. Indication of cross‐resistance was absent for the compounds evaluated against the multi‐resistant Dd2 strain. Structure‐activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α‐carbon and NH group of the α‐amino‐o‐cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor‐groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.

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Unraveling the Electronic Structure, Spin States, Optical and Vibrational Spectra of Malaria Pigment

Ali

Oppeneer

2015

Chemistry A European J

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A detailed knowledge of the electronic structure and magnetic and optical properties of hemozoin, the malaria pigment, is essential for the design of effective antimalarial drugs and malarial diagnosis. By employing state-of-the-art electronic structure calculations, we have performed an in-depth investigation of the malaria pigment. Specifically, molecular bond lengths and spin states of the two Fe(III) heme centers and their exchange interaction, the UV/Vis absorption spectrum, and the IR vibrational spectra were calculated and compared with available experimental data. Our density functional theory (DFT)-based calculations predict a singlet ground spin state that stems from an S=5/2 spin state on each of the Fe heme centers with a very weak antiferromagnetic exchange interaction between them. Our theoretical UV/Vis and IR spectra provide explanations for various spectroscopic studies of hemozoin and β-hematin (a synthetic analogue of hemozoin). A good comparison of calculated and measured properties demonstrates the convincing unveiling of the electronic structure of the malaria pigment. Based on the predicted vibrational spectra, we propose a unique spectral band from the nuclear resonance vibrational spectroscopy (NRVS) results that could be used as a key fingerprint for malarial detection.

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Structure of Malaria Pigment and Related Propanoate‐Linked Metalloporphyrin Dimers

Cited by 31 publications

References 49 publications

Hydrating the Bispropionate Notch in Malaria Pigment: A New Structural Motif in the Iron(III)(deuteroporphyrin) Dimer

Hydrating the Bispropionate Notch in Malaria Pigment: A New Structural Motif in the Iron(III)(deuteroporphyrin) Dimer

The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction

Unraveling the Electronic Structure, Spin States, Optical and Vibrational Spectra of Malaria Pigment

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