Hypericin Derivative Research Articles

Synthesis and in vitro/vivo Evaluation of Iodine-123/124 Labelled Hypericin Derivatives

To evaluate the potential of radioiodine labelled hypericin as a malignant glioma imaging agent, U-251 MG, U-373 MG, C6 glioma and fibroblast were treated with a I-123 labelled hypericin derivative and C6 glioma transplanted nude mouse were injected with a I-124 labelled hypericin derivative for a micro PET imaging. 2- Iodohypericin was prepared as a reference compound. In this paper, we describe the syntheses of 2- iodohypericin and 2-[<TEX>$^{123}I/^{124}I$</TEX>]iodohypericin and the results of a corresponding biological evaluation. In all glioma cell lines, 2-[<TEX>$^{123}I$</TEX>]iodohypericin uptake was increased in a time dependant manner and an accumulation of 2-[<TEX>$^{124}I$</TEX>]iodohypericin was observed in C6 glioma bearing nude mouse. These results suggest that radioiodine labelled hypericin can visualize a PKC overexpressed malignant glioma.

ω,ω′-Urea- and -dithioacetal-derivatives of hypericin

An ω,ω′-disubstituted hypericin derivative bearing two dicyclohexylurea moieties separated by propionyl chains from the chromophore and an ω,ω′-dithioacetal of hypericin were prepared. Both showed excellent production of oxidizing species comparable to hypericin when irradiated with appropriate light as shown by the photodestruction of bilirubin IXα.

Synthesis and preliminary biological evaluation of a 99mTc‐labeled hypericin derivative as a necrosis avid imaging agent

AbstractMono‐[123I]iodohypericin and mono‐[123I]iodohypericin monocarboxylic acid are iodine‐123‐labeled hypericin derivatives which have shown great promise in preclinical studies as necrosis avid imaging agents in animal models of infarction. In view of the more attractive properties of a 99mTc‐labeled hypericin derivative, we have synthesized a conjugate of protohypericin monocarboxylic acid with S‐benzoylmercaptoacetyldiglycyl‐diaminopentane in an overall yield of 15%. The conjugate was labeled with technetium‐99m by exchange labeling at pH 10 in a labeling yield of 95% followed by photocyclization to yield 99mTc‐mercaptoacetyldiglycyl‐1,5‐diaminopentylene hypericincarboxamide (99mTc‐13). The negatively charged 99mTc‐13 complex was purified by reversed phase high‐pressure liquid chromatography and the log P7.4 was determined to be 2.36. In normal NMRI mice, the complex showed slow hepatobiliary clearance while plasma clearance was rapid. The tracer was evaluated in rats with reperfused hepatic infarction by ex vivo autoradiography, gamma counting and histochemical techniques. Unlike the radioiodinated hypericin derivatives, the new tracer agent did not show preferential uptake in necrotic tissue on autoradiography and gamma counting techniques. Conjugation of hypericin with a 99mTc‐chelate, resulting in a change in size, charge and lipophilicity, had a profound effect on the necrosis avidity of the tracer agent. The results show that 99mTc‐13 is not suitable for imaging necrosis. Copyright © 2008 John Wiley &amp; Sons, Ltd.

Toward Hypericin-derived Potential Photodynamic Therapy Agents¶

To optimize a hypericin derivative as a potential photodynamic therapy agent its light-induced singlet oxygen/superoxide radical formation capability should be enhanced and its long-wavelength absorption band should be bathochromically shifted to better match medicinal lasers. A heavy-atom–substituted derivative was realized by electrophilic iodination of hypericin to yield 2,5-diiodo-hypericin. Using photodestruction of bilirubin IXα this derivative was demonstrated to exhibit an enhanced light-induced singlet oxygen/superoxide radical formation capability as compared to hypericin. With respect to a bathochromically shifted derivative styryl residues were attached to the methyl groups of hypericin by de novo ring synthesis. Although the long-wavelength absorption band of this derivative displayed a bathochromic shift of nearly 40 nm it unfortunately immediately underwent an intramolecular [2 + 2] cycloaddition to yield the corresponding cyclobutane derivative in which the added conjugation system became interrupted.

Condensed Emodin Derivatives and Their Applicability for the Synthesis of a Fused Heterocyclic Hypericin Derivative

AbstractInvestigations on the bifunctionalization of emodin at C(6) and C(7) with respect to the synthesis of a new class of fused heterocyclic hypericin derivatives were undertaken. The synthesis of such complex anthraquinone derivatives is possible by applying a Marschalk‐type reaction with emodin‐6‐carbaldehyde as the key step. The newly synthesized pyridazinone‐fused hypericin derivative possesses a satisfying bathochromically shifted absorption maximum making it a promising candidate for further investigations concerning a possible application in photodynamic therapy. Furthermore, the herein described strategy for the bifunctionalization of emodin provides a novel route for the synthesis of anthraquinone derivatives that are difficult to obtain by other methods.(© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis and Properties of 10,11‐Dibenzimidazolyl‐10,11‐didesmethylhypericin — The First Heterocyclically Substituted Hypericin Derivative.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Properties of 10,11-Dibenz-imidazolyl-10,11-didesmethyl-hypericin ? The First Heterocyclically Substituted Hypericin Derivative

The synthesis of the first heterocyclically substituted title hypericin derivative was achieved starting from 6-benzimidazolyl-tri-O-methyl-6-desmethylemodin. The chemical as well as photochemical properties of this unique hypericin derivative, which might constitute a new photodynamic therapy agent, are reported.

Photodynamic effect of hypericin and a water-soluble derivative on isolated crayfish neuron and surrounding glial cells

Hypericin (Hyp) has been proposed as a fluorochrome for fluorescence diagnostics and as a photosensitizer for photodynamic therapy of cancer. However, its insolubility in water is a serious drawback. A novel water-soluble hypericin derivative (Hyp-S) has been constructed, using polyvinylpyrrolidone as a carrier. We used the crayfish stretch receptor, consisting of receptor neuron and satellite glial cells, for comparison of the photodynamic effects of Hyp and Hyp-S. Hyp-S was more toxic in the dark than Hyp and inactivated the neurons at concentrations exceeding 4 μM while Hyp was toxic to the neurons only at the concentrations larger than 20 μM. Electrophysiological investigations revealed polyphasic neuron responses to photosensitization with Hyp as well as with Hyp-S (1 μM concentration, 30 min incubation; irradiation with filtered light from a lamp with an emission maximum near 600 nm and an intensity of 0.2 W/cm 2). In the concentration range 1–4 μM Hyp-S was more phototoxic than Hyp. Fluorescence microscopy showed that both sensitizers were predominately localized in the glial envelope surrounding the neuron. A minor fraction of hypericin was found in the neuron perinuclear area rich in cytoplasm organelles. This suggests the potential application of Hyp and Hyp-S for visualization and selective photodynamic treatment of malignant gliomas.

On the Chemistry of a Dibenzohypericin Derivative

A hypericin derivative was synthesized in which instead of the methyl groups two benzene rings were condensed to the chromophoric system in order to extend its conjugation. This derivative showed lowered fluorescence and concomitantly enhanced sensitized production of active oxygen species as compared to hypericin. However, in contrast to intuition its long wavelength band remained unshifted in comparison to its parent compound hypericin. Geometry and absorption properties were also investigated by means of semiempirical calculations.

Concerning the Absorption and Photochemical Properties of an ω-4-Dimethylaminobenzal Hypericin Derivative

A hypericin derivative containing ω,ω ′-4-dimethylaminobenzal residues was shown to undergo an intramolecular [2 + 2] cycloaddition upon irradiation leading to a cyclobutane derivative whose main absorption band is hardly shifted as compared to hypericin. The corresponding ω-substituted derivative displayed a 34 nm bathochromic shift and a strongly reduced fluorescence quantum yield rendering it a nice candidate for a photodynamic therapy agent. Unfortunately, however, it produced virtually no photosensitized active oxygen species, making it thus unsuited for this purpose.

Toward hypericin-derived potential photodynamic therapy agents.

To optimize a hypericin derivative as a potential photodynamic therapy agent its light-induced singlet oxygen/superoxide radical formation capability should be enhanced and its long-wavelength absorption band should be bathochromically shifted to better match medicinal lasers. A heavy-atom-substituted derivative was realized by electrophilic iodination of hypericin to yield 2,5-diiodo-hypericin. Using photodestruction of bilirubin IX alpha this derivative was demonstrated to exhibit an enhanced light-induced singlet oxygen/superoxide radical formation capability as compared to hypericin. With respect to a bathochromically shifted derivative styryl residues were attached to the methyl groups of hypericin by de novo ring synthesis. Although the long-wavelength absorption band of this derivative displayed a bathochromic shift of nearly 40 nm it unfortunately immediately underwent an intramolecular [2 + 2] cycloaddition to yield the corresponding cyclobutane derivative in which the added conjugation system became interrupted.

ChemInform Abstract: Synthesis and Properties of Hypericins Substituted with Acidic and Basic Residues: Hypericin Tetrasulfonic Acid — A Water Soluble Hypericin Derivative.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and Properties of Hypericins Substituted with Acidic and Basic Residues: Hypericin Tetrasulfonic Acid – A Water Soluble Hypericin Derivative

Sulfonation of hypericin leads to its di-, tri-, and tetrasulfonic acid derivatives. The latter is soluble in water up to millimolar solutions. Homoaggregate formation (J-aggregates) was observed only above 5ċ10−4 mol/l. In water solutions, the tetrasulfonic acid hypericin derivative was found to be present as its bay-phenolate with most of the sulphonic acids dissociated. Thus, the first water soluble hypericin derivative, which in contrast to hypericin is not prone to homoassociation, is presented. Hypericin tetrtasulfonic acid forms heteroassociates with serum albumin, DNA, and γ-cyclodextrin. Hypericin derivatives with primary and tertiary amino group appendages at the hypericin methyl groups were synthesized. However, upon salt formation or quaternization these derivatives became virtually insoluble in all common solvents including water.

The deprotonation and protonation equilibria of a hypericin derivative in aqueous solution

A hypericin derivative ω,ω'-appended at the methyl groups with two polyethylene glycol moieties (about 23 units long) and capped with acetyl groups was synthesized starting from emodin. This derivative proved to be soluble in water and was investigated by means of spectrophotometric titrations and electrophoresis experiments. Deprotonation at thebay-region hydroxyl group was observed atpKa=1.6. This was followed by a second deprotonation step of aperi-hydroxyl group at apKa value of 9.4. This derivative could be protonated at the carbonyl group characterized by apKa value of −5.7. FrompKa determinations in water-ethanol mixtures the correspondingpKa values of hypericin itself determined in such mixtures were extrapolated to the aqueous phase. This resulted in estimatedpKa values of 1.8, 9.2, and −6.

ChemInform Abstract: Synthesis and Properties of an ω,ω′‐Appended Eighteen Carbon Chains Hypericin Derivative.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Structural aspects and electronic absorption of the hydroxyphenanthroperylene quinones fringelit D, hypericin, and stentorin

PPP type semiempirical quantum chemical calculations of absorption spectra were performed for hypericin, fringelit D, stentorin, and their respective conformers, tautomers, and deprotonated species. The results agree with the experimental absorption spectra of hypericin, stentorin, and fringelit D, their deprotonated species, and the polarized absorption spectra of an ω,ω′-long chain appended hypericin derivative embedded in stretched polyethylene.