Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB)
Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/22/12371 |
| _version_ | 1797509970377310208 |
|---|---|
| author | Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Zhela L. Sabir Lech J. P. Staniszewski Ankedo Warda Emma L. Maiorella Ani Minasian Jesse Davidson Samir J. Ibrahim San Raban Dena Haddad Madleen Khamisi Stephanie L. Suban Bradley J. Dawson Riley Candia Joseph W. Ziller Ming-Yue Lee Chang Liu Wei Liu Pamela A. Marshall John S. Welch Carl E. Wagner |
| author_facet | Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Zhela L. Sabir Lech J. P. Staniszewski Ankedo Warda Emma L. Maiorella Ani Minasian Jesse Davidson Samir J. Ibrahim San Raban Dena Haddad Madleen Khamisi Stephanie L. Suban Bradley J. Dawson Riley Candia Joseph W. Ziller Ming-Yue Lee Chang Liu Wei Liu Pamela A. Marshall John S. Welch Carl E. Wagner |
| author_sort | Peter W. Jurutka |
| collection | DOAJ |
| description | Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (<b>1</b>), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC<sub>50</sub> and IC<sub>50</sub> values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as <b>1</b>. |
| first_indexed | 2024-03-10T05:25:17Z |
| format | Article |
| id | doaj.art-0e2a47cceb6e4307aef298907165189b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:25:17Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0e2a47cceb6e4307aef298907165189b2023-11-22T23:41:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122221237110.3390/ijms222212371Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB)Peter W. Jurutka0Orsola di Martino1Sabeeha Reshi2Sanchita Mallick3Zhela L. Sabir4Lech J. P. Staniszewski5Ankedo Warda6Emma L. Maiorella7Ani Minasian8Jesse Davidson9Samir J. Ibrahim10San Raban11Dena Haddad12Madleen Khamisi13Stephanie L. Suban14Bradley J. Dawson15Riley Candia16Joseph W. Ziller17Ming-Yue Lee18Chang Liu19Wei Liu20Pamela A. Marshall21John S. Welch22Carl E. Wagner23School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USADepartment of Internal Medicine, Washington University, St. Louis, MO 63110, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USADepartment of Chemistry, University of California, Irvine, CA 92697, USASchool of Molecular Sciences, Arizona State University, Tempe, AZ 85201, USASchool of Molecular Sciences, Arizona State University, Tempe, AZ 85201, USASchool of Molecular Sciences, Arizona State University, Tempe, AZ 85201, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USADepartment of Internal Medicine, Washington University, St. Louis, MO 63110, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USAFive novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (<b>1</b>), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC<sub>50</sub> and IC<sub>50</sub> values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as <b>1</b>.https://www.mdpi.com/1422-0067/22/22/12371retinoid-X-receptorretinoidrexinoidleukemiasmall molecule therapeuticstructure–activity relationship |
| spellingShingle | Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Zhela L. Sabir Lech J. P. Staniszewski Ankedo Warda Emma L. Maiorella Ani Minasian Jesse Davidson Samir J. Ibrahim San Raban Dena Haddad Madleen Khamisi Stephanie L. Suban Bradley J. Dawson Riley Candia Joseph W. Ziller Ming-Yue Lee Chang Liu Wei Liu Pamela A. Marshall John S. Welch Carl E. Wagner Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB) International Journal of Molecular Sciences retinoid-X-receptor retinoid rexinoid leukemia small molecule therapeutic structure–activity relationship |
| title | Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB) |
| title_full | Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB) |
| title_fullStr | Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB) |
| title_full_unstemmed | Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB) |
| title_short | Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB) |
| title_sort | modeling synthesis and biological evaluation of potential retinoid x receptor rxr selective agonists analogs of 4 1 3 5 5 8 8 pentamethyl 5 6 7 8 tetrahyro 2 naphthyl ethynyl benzoic acid bexarotene and 6 ethyl 4 isobutoxy 3 isopropylphenyl amino nicotinic acid net 4ib |
| topic | retinoid-X-receptor retinoid rexinoid leukemia small molecule therapeutic structure–activity relationship |
| url | https://www.mdpi.com/1422-0067/22/22/12371 |
| work_keys_str_mv | AT peterwjurutka modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT orsoladimartino modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT sabeehareshi modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT sanchitamallick modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT zhelalsabir modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT lechjpstaniszewski modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT ankedowarda modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT emmalmaiorella modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT animinasian modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT jessedavidson modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT samirjibrahim modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT sanraban modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT denahaddad modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT madleenkhamisi modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT stephanielsuban modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT bradleyjdawson modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT rileycandia modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT josephwziller modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT mingyuelee modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT changliu modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT weiliu modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT pamelaamarshall modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT johnswelch modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib AT carlewagner modelingsynthesisandbiologicalevaluationofpotentialretinoidxreceptorrxrselectiveagonistsanalogsof4135588pentamethyl5678tetrahyro2naphthylethynylbenzoicacidbexaroteneand6ethyl4isobutoxy3isopropylphenylaminonicotinicacidnet4ib |