Syntheses and Properties of Two Heterocyclically Substituted Hypericin Derivatives: 10,11-Dibenzothiazolyl-10,11-didemethylhypericin and 10,11-Dibenzoxazolyl-10,11-didemethylhypericin

Lackner, Bernd; Popova, Yulita; Etzlstorfer, Christoph; Šmelcerović, Andrija; Klampfl, Christian W.; Falk, Heinz

doi:10.1007/s00706-004-0275-6

Cited by 9 publications

(6 citation statements)

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“…Falk and co-workers, renowned for their research in hypericin synthesis and the elucidation of the physicochemical properties of this molecule, developed a new class of modified hypericin derivatives, which contained extra heterocyclic rings such as benzothiazolyl, benzoxazolyl [ 60 ] and benzothiazole [ 61 ]. Basic concept of these syntheses was that the methyl groups of the hypericin moiety served as “anchors” for the substitution by the extra chromophore units.…”

Section: Extraction Isolation and Synthesis Of Hypericin And Pseudohmentioning

confidence: 99%

Hypericins as Potential Leads for New Therapeutics

Karioti

Bilia

2010

IJMS

250

191

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70 years have passed since the first isolation of the naphthodianthrones hypericin and pseudohypericin from Hypericum perforatum L. Today, they continue to be one of the most promising group of polyphenols, as they fascinate with their physical, chemical and important biological properties which derive from their unique chemical structure. Hypericins and their derivatives have been extensively studied mainly for their antitumor, antiviral and antidepressant properties. Notably, hypericin is one of the most potent naturally occurring photodynamic agents. It is able to generate the superoxide anion and a high quantum yield of singlet oxygen that are considered to be primarily responsible for its biological effects. The prooxidant photodynamic properties of hypericin have been exploited for the photodynamic therapy of cancer (PDT), as hypericin, in combination with light, very effectively induces apoptosis and/or necrosis of cancer cells. The mechanism by which these activities are expressed continues to be a main topic of discussion, but according to scientific data, different modes of action (generation of ROS & singlet oxygen species, antiangiogenesis, immune responces) and multiple molecular pathways (intrinsic/extrinsic apoptotic pathway, ERK inhibition) possibly interrelating are implicated. The aim of this review is to analyse the most recent advances (from 2005 and thereof) in the chemistry and biological activities (in vitro and in vivo) of the pure naphthodianthrones, hypericin and pseudohypericin from H. perforatum. Extracts from H. perforatum were not considered, nor pharmakokinetic or clinical data. Computerised literature searches were performed using the Medline (PubMed), ChemSciFinder and Scirus Library databases. No language restrictions were imposed.

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Section: Extraction Isolation and Synthesis Of Hypericin And Pseudohmentioning

confidence: 99%

Hypericins as Potential Leads for New Therapeutics

Karioti

Bilia

2010

IJMS

250

191

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“…To avoid a cycloaddition between the two adjacent double bonds in the corresponding hypericin derivatives, the products 3 and 4 thus available in modest yields could be easily and nearly quantitatively hydrogenated using palladium on charcoal as catalyst and methanol as solvent under ambient conditions to 5 and 6. The latter were deprotected and reduced in acceptable yields to the anthrone derivatives 7 and 8 in the common way (12)(13)(14)(15)(16)(17) using SnCl 2 ⁄ HBr in glacial acetic acid. Dimerization by means of Fe(SO 4 ) 2 ⁄ pyridine-N-oxide in pyridine and piperidine as the catalyst (12)(13)(14)(15)(16)(17) provided the protohypericin derivatives 9 and 10, which were immediately photocyclized to the hypericin derivatives 11 and 12.…”

Section: Synthesismentioning

confidence: 99%

“…During the last decade its fundamental chromophore has been derivatized in order to generate second-generation agents (11). These efforts resulted in analogs with redshifted absorption spectra to provide compounds excitable at wavelengths with enhanced penetration depth on the one hand (12)(13)(14)(15)(16)(17), and better physicochemical properties, e.g. higher solubility under physiological conditions or targeting of specific cellular sites, on the other hand (18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

“…>350°C; 1 H NMR (500 MHz, MeOH-d 4 , 30°C): d = 7.58 (s, ar-H9 and ar-H12), 7,52 (d, J = 4.0 Hz, 2Py-H2,6), 6.79 (s, ar-H2 and ar-H5), 6.63 (d, J = 4.0 Hz, 2Py-H3,5), 3.11 (m, 4H, 10-CH 2 -CH 2 -and 11-CH 2 -CH 2 -), 2.46 (m, 4H, 10-CH 2 -CH 2 -and 11-CH 2 -CH 2 -) ppm (OH signals were not found due to H ⁄ D exchange); IR (KBr): m = 3418, 3075, 2947, 2834, 1600, 1504, 1464, 1427, 1250, 1188, 1115, 1029, 848, 802 cm )1 ; UV-Vis (methanol; c = 2.20AE10 )4 M M): k max (e ⁄ L mol )1 cm )1 ) = 329 (2278), 381 (1128), 446 (1028), 475 (1110), 511 (841), 548 (1737), 592 nm (3147); fluorescence (methanol; c = 1.03AE10 )5 M M, k ex = 550 nm): k em (rel. intensity) = 595 (100), 644 nm (30) ⁄ F f = 0.1; MS (ESI-MS; MeOH; c 1 mgAEcm )3 ; negative ion mode): m ⁄ z = 685 ([M-H]) ) .3,4-bis(4-(Dimethylamino)phenethyl)-1,6,8,10,11,13-hexa-hydroxyphenanthro[1,10,9,8-opqra]perylen-7,14-dione(12). Prepared from 10 in analogy to 11 and obtained in 27% yield (based on 10), C 48 H38 N 2 O 8 : m.p.…”

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confidence: 99%

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Cationic Hypericin Derivatives as Novel Agents with Photobactericidal Activity: Synthesis and Photodynamic Inactivation of Propionibacterium acnes

Hager

Strauß

Falk

2009

Photochem & Photobiology

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The present communication describes for the first time the synthesis and preliminary testing of two cationic hypericin derivatives. Uncharged hypericin derivatives with omega,omega'-attached C2-linkers leading to a pyridyl or a 4-dimethylaminophenyl residue were prepared and subsequently quaternized by means of iodomethane. Photobactericidal activity was assessed using Propionibacterium acnes. The quaternary N,N,N-trimethyl-anilinium derivative displayed a pronounced photodynamic inactivation of the bacteria at low incubation concentrations (<100 nm) and a short incubation time (1 h) after illumination with yellow light (590 nm, 20 J cm(-2)), whereas the photobactericidal efficacy of the N-methyl-pyridinium derivative was negligible under identical experimental conditions.

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“…Hypericin and seven derivatives were prepared as described earlier. [12][13][14][15][16][17] Stock solutions of 10 mM were made in dimethyl sulfoxide (DMSO) and stored at -20 • C under dark circumstances. All compounds were manipulated under subdued light conditions (<1 mW cm -2 ).…”

Section: Experimental Photosensitizersmentioning

confidence: 99%

In vitro study of the photocytotoxicity of bathochromically-shifted hypericin derivatives

Roelants

Lackner

Waser

et al. 2009

Photochem Photobiol Sci

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Hypericin has excellent photosensitizing properties and displays favorable tumouritropic characteristics, but at the same time exhibits minimal dark toxicity. As such, the compound is a promising photosensitizer in the context of clinical photodynamic therapy (PDT). The present study was undertaken to investigate whether a newly-synthesized series of hypericin derivatives with a bathochromic shift shows promise for future PDT applications. Potentially these structures offer an advantage over the parent compound by being photo-activated by red light, which penetrates deeper into tumour tissue. Our results show that 3 compounds (a dibenzoxazole, a pyridazinone, and especially a dibenzthiazole derivative of hypericin), designed to exhibit a bathochromic shift in their absorption spectrum, demonstrated an efficient singlet oxygen yield and intracellular uptake, and concomitantly a potent photocytotoxic effect under white-light conditions. These results indicate that it is possible to synthesize bathochromically-shifted compounds based on hypericin chemistry which maintain their PDT potential. However, the data also show that the present derivatives are only poor photosensitizers when used under red-light conditions.

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Syntheses and Properties of Two Heterocyclically Substituted Hypericin Derivatives: 10,11-Dibenzothiazolyl-10,11-didemethylhypericin and 10,11-Dibenzoxazolyl-10,11-didemethylhypericin

Cited by 9 publications

References 0 publications

Hypericins as Potential Leads for New Therapeutics

Hypericins as Potential Leads for New Therapeutics

Cationic Hypericin Derivatives as Novel Agents with Photobactericidal Activity: Synthesis and Photodynamic Inactivation of Propionibacterium acnes

In vitro study of the photocytotoxicity of bathochromically-shifted hypericin derivatives

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