Rational Design, Synthesis and Binding Affinity Studies of Anthraquinone Derivatives Conjugated to Gonadotropin-Releasing Hormone (GnRH) Analogues towards Selective Immunosuppression of Hormone-Dependent Cancer

Author:

Biniari Georgia1ORCID,Markatos Christos2ORCID,Nteli Agathi1ORCID,Tzoupis Haralambos1ORCID,Simal Carmen1ORCID,Vlamis-Gardikas Alexios1ORCID,Karageorgos Vlasios2,Pirmettis Ioannis3ORCID,Petrou Panagiota3,Venihaki Maria4ORCID,Liapakis George2,Tselios Theodore1ORCID

Affiliation:

1. Department of Chemistry, University of Patras, 26504 Rion, Greece

2. Department of Pharmacology, School of Medicine, University of Crete, 71003 Heraklion, Greece

3. Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research “Demokritos”, 15341 Athens, Greece

4. Department of Clinical Chemistry, School of Medicine, University of Crete, 71003 Heraklion, Greece

Abstract

Gonadotropin-releasing hormone (GnRH) is pivotal in regulating human reproduction and fertility through its specific receptors. Among these, gonadotropin-releasing hormone receptor type I (GnRHR I), which is a member of the G-protein-coupled receptor family, is expressed on the surface of both healthy and malignant cells. Its presence in cancer cells has positioned this receptor as a primary target for the development of novel anti-cancer agents. Moreover, the extensive regulatory functions of GnRH have underscored decapeptide as a prominent vehicle for targeted drug delivery, which is accomplished through the design of appropriate conjugates. On this basis, a rationally designed series of anthraquinone/mitoxantrone–GnRH conjugates (con1–con8) has been synthesized herein. Their in vitro binding affinities range from 0.06 to 3.42 nM, with six of them (con2–con7) demonstrating higher affinities for GnRH than the established drug leuprolide (0.64 nM). Among the mitoxantrone based GnRH conjugates, con3 and con7 show the highest affinities at 0.07 and 0.06 nM, respectively, while the disulfide bond present in the conjugates is found to be readily reduced by the thioredoxin (Trx) system. These findings are promising for further pharmacological evaluation of the synthesized conjugates with the prospect of performing future clinical studies.

Funder

European Union and the Greek National Funds

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference92 articles.

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2. Hypothalamic Factors Which Influence Gonadotrophin Secretion;McCann;Trans. N. Y. Acad. Sci.,1964

3. Synthesis and Secretion of GnRH;Clarke;Anim. Reprod. Sci.,2005

4. Isolation and Properties of the FSH and LH-Releasing Hormone;Schally;Biochem. Biophys. Res. Commun.,1971

5. Role of FSH in Male Gonadal Function;Simoni;Ann. Endocrinol.,1999

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