Synthesis of Gonadotropin-Releasing Hormone III Analogs. Structure−Antitumor Activity Relationships

Mezö, Imre; Lovas, Sándor; Pályi, I; Vincze, B.; Kalnay, A.; Turi, Gabriele; Vadász, Zsolt; Seprödi, János; Idei, Miklós; Tóth, Gy.; Gulyás, Éva; Ötvös, Ferenc; Mák, Marianna; Horváth, Judit; Teplán, István; Murphy, Richard F.

doi:10.1021/jm9801152

Cited by 5 publications

(10 citation statements)

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“…The structure-antitumor relationships of the GnRH-III analogs synthesized by Mező and coworkers suggest the contribution of the indol rings of Trp 3,7 to the interaction of GnRH-III with the receptor. The cleavage of Trp 3 might interfere with the receptor binding of the GnRH-III fragment [12]. It is also conceivable that the deletion of the Glp-His-Trp tripeptide from the N-terminal part changes drastically the structure and consequently the behavior of the molecule.…”

Section: Discussionmentioning

confidence: 99%

“…All the facts mentioned earlier might indicate that GnRH-III is the most effective and selective native GnRH analog able of inhibiting the tumor growth [17]. Previous studies on structure-activity relationship indicated that the modification of the Lys 8 in GnRH-III did not result in the loss of receptor binding and antiproliferative effect [12,16,18,19]. Furthermore, the elimination of the free e-amino group resulted in the decrease of endocrine effect of the parent hormone peptide [16,20].…”

Section: Introductionmentioning

confidence: 95%

“…However, it is widely accepted that the antitumor effect of the GnRH derivatives might be also mediated by a direct action, via the GnRH-Rs that are highly expressed in many cancer tissues either related (prostate, breast, ovarian, and endometrial) or unrelated (melanoma, colon, lung, pancreatic, etc.) to the reproductive system [6,[10][11][12]. Therefore, the GnRH-Rs represent a good target for selective drug delivery.…”

Section: Introductionmentioning

confidence: 99%

“…However, these compounds have significant endocrine effect that is not always favorable in tumor therapy, especially not in the case of the treatment of hormone-independent tumors. To avoid the endocrine side effects, the GnRH-III related peptides were developed [12].…”

Section: Introductionmentioning

confidence: 99%

“…GnRH-III is not a natural ligand of the human GnRH-R, but it binds specifically to the GnRH-Rs on cancer cells. In this way, GnRH-III directly inhibits the growth of the GnRH-R positive tumors [12]. Besides its remarkable antiproliferative effect, GnRH-III has low endocrine potency in mammals [16], and it does not contain any D-amino acids or nonnatural amino acids, which are associated with numerous allergic side effects of synthetic derivatives with potent antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

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Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH‐III derivatives in Tetrahymena and human leukemia cell line

Lajkó

Szabó

Andódy

et al. 2012

Journal of Peptide Science

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GnRH-III has been shown to exert a cytotoxic effect on the GnRH-R positive tumor cells. The chemotactic drug targeting (CDT) represents a new way for drug delivery approach based on selective chemoattractant guided targeting. The major goal of the present work was to develop and investigate various GnRH-III derivatives as potential targeting moieties for CDT. The cell physiological effects (chemotaxis, adhesion, and signaling) induced by three native GnRHs (hGnRH-I, cGnRH-II, and lGnRH-III) and nine GnRH-III derivatives were evaluated in two model cells (Tetrahymena pyriformis and Mono Mac 6 human monocytes). According to our results, the native GnRH-III elicited the highest chemoattractant and adhesion inducer activities of all synthesized peptides in micromolar concentrations in monocytes. With respect to chemoattraction, dimeric derivatives linked by a disulfide bridge ([GnRH-III(C)](2) ) proved to be efficient in both model cells; furthermore, acetylation of the linker region ([GnRH-III(Ac-C)](2) ) could slightly improve the chemotactic and adhesion effects in monocytes. The length of the peptide and the type of N-terminal amino acid could also determine the chemotactic and adhesion modulation potency of each fragment. The application of the chemoattractant GnRH-III derivatives was accompanied by a significant activation of phosphatidylinositol 3-kinase in both model cells. In summary, our work on low-level differentiated model cells of tumors has proved that GnRH-III and some of its synthetic derivatives are promising candidates to be applied in CDT: these compounds might act both as carrier, delivery unit, and antitumor agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH‐III derivatives in Tetrahymena and human leukemia cell line

Lajkó

Szabó

Andódy

et al. 2012

Journal of Peptide Science

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Synthesis and structural characterization of bioactive peptide conjugates using thioether linkage approaches

Mező

Manea

Jakab

et al. 2004

Journal of Peptide Science

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Applications of cysteine-insertion and thioether linkage approaches to the preparation of a number of bioactive peptide conjugates are reported. Peptides containing epitopes from (i) herpes simplex virus type 1 glycoprotein D, (ii) a specific N-terminal beta-amyloid epitope recognized by therapeutically active antibodies, and (iii) a GnRH-III peptide from sea lamprey with antitumour activity, were elongated with Cys residues and attached to a chloroacetylated tetratuftsin derivative carrier via a thioether linkage either directly, or by insertion of a spacer. The structures and molecular homogeneity of all the peptide conjugates were ascertained by HPLC, MALDI and electrospray mass spectrometry. The use of a spacer such as an oligoglycine or GFLG-tetrapeptide gave an increased yield in the conjugation reaction and enhanced reaction rates. In the formation of cysteinyl-thioether linkages, it was found that the position of flanking Cys residues markedly influenced the conjugation reaction and the formation of intermolecular epitope disulfide-dimers. C-terminal Cys residues gave thioether conjugates with significantly diminished epitope-dimerization, while Cys at the N-terminal caused rapid disulfide-dimerization, thereby preventing efficient conjugation.

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Development of an Oxime Bond Containing Daunorubicin-Gonadotropin-Releasing Hormone-III Conjugate as a Potential Anticancer Drug

et al. 2009

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Here, we report on the synthesis and biological properties of a conjugate in which daunorubicin (Dau) as chemotherapeutic agent was attached through an oxime bond to gonadotropin-releasing hormone-III (GnRH-III) as targeting moiety. In vitro toxicity and the cytostatic effect of the conjugate on MCF-7 human breast and C26 murine colon cancer cell lines were determined, and the results were compared with those obtained for the free daunorubicin, as well as with the doxorubicin containing derivative. In vivo antitumor effect of daunorubicin-GnRH-III was studied on Balb/c female mice transplanted with C26 tumor. Our data indicate that the daunorubicin-GnRH-III conjugate had a lower toxic effect than the free daunorubicin and it was essentially nontoxic up to 15 mg (Dau content)/kg body weight. The treatment of the C26 tumor bearing mice with the conjugate led to tumor growth inhibition and longer survival time in comparison with the controls and with the administration of the free drug. When mice were treated twice with the conjugate (on days 4 and 7 after tumor transplantation), 46% tumor growth inhibition was obtained. In this case, the increase of the median survival time was 38% compared to the controls.

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Synthesis of Gonadotropin-Releasing Hormone III Analogs. Structure−Antitumor Activity Relationships

Cited by 5 publications

References 0 publications

Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH‐III derivatives in Tetrahymena and human leukemia cell line

Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH‐III derivatives in Tetrahymena and human leukemia cell line

Synthesis and structural characterization of bioactive peptide conjugates using thioether linkage approaches

Development of an Oxime Bond Containing Daunorubicin-Gonadotropin-Releasing Hormone-III Conjugate as a Potential Anticancer Drug

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