Cytotoxic peptides: Naphthoquinonyl derivatives of luteinizing hormone-releasing hormone

Rahimipour, Shai; Weiner, Lev; Shrestha‐Dawadi, Prativa Bade; Bittner, Shmuel; Koch, Yitzhak; Fridkin, Mati

doi:10.1007/bf02443499

Cited by 8 publications

(15 citation statements)

References 24 publications

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“…In order to add new members to this promising chemical series to define the critical structural elements required for potency and selectivity, we are interested in evaluating substances containing biologically relevant nitrogen substituents such as natural α-amino acids. Concerning the design of isoquinolinequinone-α-amino acid derivatives, it was based on the cytotoxic activity of α-amino acid-containing natural occurring 1,4-benzoquinones [14,15,16], 1,4-naphthoquinone [17,18,19], and 9,10-anthraquinone [20].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone–Amino Acid Derivatives

et al. 2016

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A variety of aminoisoquinoline-5,8-quinones bearing α-amino acids moieties were synthesized from 3-methyl-4-methoxycarbonylisoquinoline-5,8-quinone and diverse L-and D-α-amino acid methyl esters. The members of the series were evaluated for their cytotoxic activity against normal and cancer cell lines by using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. From the current investigation, structure-activity relationships demonstrate that the location and structure of the amino acid fragment plays a significant role in the cytotoxic effects. Moderate to high cytotoxic activity was observed and four members, derived from L-alanine, L-leucine, L-phenylalanine, and D-phenylalanine, were selected as promising compounds by their IC 50 ranging from 0.5 to 6.25 µM and also by their good selectivity indexes (≥2.24).

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Section: Introductionmentioning

confidence: 99%

Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone–Amino Acid Derivatives

et al. 2016

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“…The mixture was then analyzed by analytical HPLC. The HPLC results show that less than 3% of [D-Lys 6 (Emo)]GnRH was degraded by the generation of ROS, similar to other cytotoxic derivatives of [D-Lys 6 ]GnRH (30).…”

Section: Dmso ϩ˙Oh →˙Ch ϩ Hos(o)chmentioning

confidence: 85%

“…[D-Lys 6 ]GnRH was synthesized on an automatic multiple peptide synthesizer (AMS-422, Abimed Analysen-Technik GmbH, Langenfeld, Germany) with Rink amide resin as a polymeric support following the company's protocol for Fmoc strategy as described (29,30). To a dimethylformamide (DMF) solution (1 mL) of the dried peptide (31 mg, 25 mol) and Emo (8.25 mg, 27.5 mol) containing 4-methylmorpholine (NMM) (8.2 L, 75 mol), a DMF solution (0.5 mL) of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (13 mg, 27.5 mol) was added.…”

Section: [D-lys 6 (6-oxy-138-trihydroxy Anthraquinone)]gnrh ([D-lysmentioning

confidence: 99%

“…The conjugate was purified to homogeneity (Ն97%) by semipreparative HPLC and characterized by analytical HPLC, UV, mass spectrometry and amino acid analysis. This method is a 'one-pot synthesis' which results in better yield (Ͼ60%) and purity as compared with other methods that use active esters such as N-hydroxysuccininide as coupling reagents (30). The efficacy of this method may be attributed to the minimization of side reactions such as those occurring at the hydroxylic function of Tyr and Ser.…”

Section: Synthesismentioning

confidence: 99%

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Generation of Free Radicals by Emodic Acid and its [d-Lys6]GnRH-conjugate¶

Rahimipour

Bilkis

Péron

et al. 2007

Photochemistry and Photobiology

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In an attempt to develop an efficient chemotherapeutic agent targeted at malignant cells that express receptors to gonadotropin releasing hormone (GnRH) we coupled [D-Lys 6 ]GnRH covalently to an emodin derivative, i.e. emodic acid (Emo) to yield [D-Lys 6 (Emo)]GnRH. Emodin is a naturally occurring anthraquinone which is widely used as a laxative and has other versatile biological activities. Physico-chemical studies employing electron paramagnetic resonance and electrochemistry of the conjugate as well as the (Emo) moiety showed that these compounds could be easily reduced either chemically, photochemically or enzymatically to their corresponding semiquinones. In the presence of oxygen the semiquinones generated reactive oxygen species (ROS), mainly superoxide and hydroxyl radicals, which were detected by the spin trapping method. Moreover, upon irradiation with visible light these compounds produced ROS and a highly reactive excited triplet state of Emo, which by itself may cause the oxidation of certain electron acceptors such as amino acids and bases of nucleic acids. Thus, [D-Lys 6 ]GnRH-photosensitizer conjugates may be potentially used for targeted photodynamic chemotherapy aimed at treating cancer cells that carry GnRH receptors. These conjugates may also induce cytotoxicity in the dark similar to common conventional chemotherapeutic agents. The peptidic moiety, [D-Lys 6 ]GnRH, was found to be stable toward highly reactive ROS generated either from enzymatic reduction or upon photoirradiation. The physico-chemical properties of Emo were only marginally influenced by the peptidic [D-Lys 6 ]GnRH carrier. ¶Posted on the website on

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“…Within the framework of target chemotherapeutic agents, a number of studies on the synthesis of cytotoxic carbocyclic quinones linked to amino acid or dipeptide fragments have been reported [ 23 , 24 , 25 , 26 , 27 ]. In this context, we have recently undertaken the synthesis of highly cytotoxic isoquinolinequinone α-amino ester conjugates [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Access to New Cytotoxic Quinone-Amino Acid Conjugates Linked through A Vinylic Spacer from 2-Acylnaphthoquinones and Methyl 3-Aminocrotonate

et al. 2017

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The reaction of 2-acetyl- and 2-benzoyl-1,4-naphthoquinone with (Z)-methyl 3-(hydroxymethyl)aminocrotonate proceeds through a formal [3+3] process to yield the corresponding 1,2-dihydrobenzisoquinolinequinones in 63% and 72% yield, respectively. The reactions of 2-acyl-1,4-naphthoquinone with enaminones, derived from diverse l- and d-amino acid methyl esters, produced the corresponding naphthoquinone amino acids conjugates bonded through a vinyl spacer in the yields range 40–71%. The presence of not-separable isomers of the naphthoquinone amino acids conjugates in the 1H- and 13C-NMR spectra is explained by the existence of conformational isomers generated by hindered rotation of the substituent bonded to the quinone double bond. These new naphthoquinone amino acids conjugates were screened in vitro on normal and cancer cell lines and showed moderate cytotoxic activities.

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Cytotoxic peptides: Naphthoquinonyl derivatives of luteinizing hormone-releasing hormone

Cited by 8 publications

References 24 publications

Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone–Amino Acid Derivatives

Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone–Amino Acid Derivatives

Generation of Free Radicals by Emodic Acid and its [d-Lys6]GnRH-conjugate¶

Access to New Cytotoxic Quinone-Amino Acid Conjugates Linked through A Vinylic Spacer from 2-Acylnaphthoquinones and Methyl 3-Aminocrotonate

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