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Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds

Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-conne...

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Autores principales: Molnár, Barnabás, Gopisetty, Mohana Krishna, Adamecz, Dóra Izabella, Kiricsi, Mónika, Frank, Éva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571145/
https://www.ncbi.nlm.nih.gov/pubmed/32899643
http://dx.doi.org/10.3390/molecules25184039
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author Molnár, Barnabás
Gopisetty, Mohana Krishna
Adamecz, Dóra Izabella
Kiricsi, Mónika
Frank, Éva
author_facet Molnár, Barnabás
Gopisetty, Mohana Krishna
Adamecz, Dóra Izabella
Kiricsi, Mónika
Frank, Éva
author_sort Molnár, Barnabás
collection PubMed
description Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-connected 2-pyrazoles of estradiol and, for comparison, their structurally simplified non-steroidal pairs were synthesized from estradiol 3-methyl ether and 6-methoxy-1,2,3,4-tetrahydronaphthalene. Friedel-Crafts acetylation of the protected phenolic compounds and subsequent O-demethylation led to ortho-substituted derivatives regioselectively, which were converted to arylhydrazones with phenylhydrazine, 4-tolylhydrazine and 4-chloro-phenylhydrazine, respectively, under microwave conditions. The hydrazones were subjected to cyclization with the Vilsmeier-Haack reagent immediately after preparation and the ring closure/formylation sequence resulted in steroidal and non-steroidal 4′-formylpyrazoles in moderate to good yields. During reductive transformations, 4-hydroxymethyl-pyrazoles were obtained, while oxidative lactonization of the 4-formylpyrazole moiety with the phenolic OH in the presence of the Jones reagent afforded A-ring-integrated pyrazolocoumarin hybrids and related analogs. Steroidal pyrazoles, which were produced as C-17 acetates due to acetylation of C-17 OH during the primary Friedel-Crafts reaction, underwent deacetylation in alkaline methanol to furnish 2-heterocyclic estradiol derivatives. Pharmacological studies revealed the overall and cancer cell-specific cytotoxicity of the derivatives and the half maximal inhibitory concentrations were obtained for the most promising compounds.
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spelling pubmed-75711452020-10-28 Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds Molnár, Barnabás Gopisetty, Mohana Krishna Adamecz, Dóra Izabella Kiricsi, Mónika Frank, Éva Molecules Article Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-connected 2-pyrazoles of estradiol and, for comparison, their structurally simplified non-steroidal pairs were synthesized from estradiol 3-methyl ether and 6-methoxy-1,2,3,4-tetrahydronaphthalene. Friedel-Crafts acetylation of the protected phenolic compounds and subsequent O-demethylation led to ortho-substituted derivatives regioselectively, which were converted to arylhydrazones with phenylhydrazine, 4-tolylhydrazine and 4-chloro-phenylhydrazine, respectively, under microwave conditions. The hydrazones were subjected to cyclization with the Vilsmeier-Haack reagent immediately after preparation and the ring closure/formylation sequence resulted in steroidal and non-steroidal 4′-formylpyrazoles in moderate to good yields. During reductive transformations, 4-hydroxymethyl-pyrazoles were obtained, while oxidative lactonization of the 4-formylpyrazole moiety with the phenolic OH in the presence of the Jones reagent afforded A-ring-integrated pyrazolocoumarin hybrids and related analogs. Steroidal pyrazoles, which were produced as C-17 acetates due to acetylation of C-17 OH during the primary Friedel-Crafts reaction, underwent deacetylation in alkaline methanol to furnish 2-heterocyclic estradiol derivatives. Pharmacological studies revealed the overall and cancer cell-specific cytotoxicity of the derivatives and the half maximal inhibitory concentrations were obtained for the most promising compounds. MDPI 2020-09-04 /pmc/articles/PMC7571145/ /pubmed/32899643 http://dx.doi.org/10.3390/molecules25184039 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Molnár, Barnabás
Gopisetty, Mohana Krishna
Adamecz, Dóra Izabella
Kiricsi, Mónika
Frank, Éva
Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds
title Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds
title_full Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds
title_fullStr Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds
title_full_unstemmed Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds
title_short Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds
title_sort multistep synthesis and in vitro anticancer evaluation of 2-pyrazolyl-estradiol derivatives, pyrazolocoumarin-estradiol hybrids and analogous compounds
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571145/
https://www.ncbi.nlm.nih.gov/pubmed/32899643
http://dx.doi.org/10.3390/molecules25184039
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