Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ER&#945; modulators (<b>4</b> and <b>5</b>) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative <b>5a</b> showed the highest binding aff...

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Main Authors: Kiminori Ohta, Asako Kaise, Fumi Taguchi, Sayaka Aoto, Takumi Ogawa, Yasuyuki Endo
Format: Article
Language:English
Published: MDPI AG 2019-11-01
Series:Molecules
Subjects:
sulfur
anticancer
estrogen
Online Access:https://www.mdpi.com/1420-3049/24/21/3966
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spelling doaj-a8eddd8285544818a8d04e429bfae35b2020-11-25T02:27:40ZengMDPI AGMolecules1420-30492019-11-012421396610.3390/molecules24213966molecules24213966Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of AntiestrogensKiminori Ohta0Asako Kaise1Fumi Taguchi2Sayaka Aoto3Takumi Ogawa4Yasuyuki Endo5School of Pharmacy, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 142-8555, JapanFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, JapanFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, JapanFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, JapanFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, JapanFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, JapanBased upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ER&#945; modulators (<b>4</b> and <b>5</b>) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative <b>5a</b> showed the highest binding affinity toward ER&#945; because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative <b>5d</b> maintained high binding affinity to ER&#945; and potently inhibited MCF-7 cell proliferation (IC<sub>50</sub>: 0.09 &#956;M). Docking simulation studies of compound <b>5d</b> with the ER&#945; BD revealed that the large hydrophobic moiety of compound <b>5d</b> fit well into the hydrophobic pocket of the ER&#945; LBD and that the sulfur atom of compound <b>5d</b> formed a sulfur&#8722;&#960; interaction with the amino acid residue His524 of the ER&#945; LBD. These interactions play important roles for the binding affinity of compound <b>5d</b> to the ER&#945; LBD.https://www.mdpi.com/1420-3049/24/21/3966sulfuranticancerestrogen
collection DOAJ
language English
format Article
sources DOAJ
author Kiminori Ohta
Asako Kaise
Fumi Taguchi
Sayaka Aoto
Takumi Ogawa
Yasuyuki Endo
spellingShingle Kiminori Ohta
Asako Kaise
Fumi Taguchi
Sayaka Aoto
Takumi Ogawa
Yasuyuki Endo
Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens
Molecules
sulfur
anticancer
estrogen
author_facet Kiminori Ohta
Asako Kaise
Fumi Taguchi
Sayaka Aoto
Takumi Ogawa
Yasuyuki Endo
author_sort Kiminori Ohta
title Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens
title_short Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens
title_full Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens
title_fullStr Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens
title_full_unstemmed Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens
title_sort design and synthesis of novel breast cancer therapeutic drug candidates based upon the hydrophobic feedback approach of antiestrogens
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2019-11-01
description Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ER&#945; modulators (<b>4</b> and <b>5</b>) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative <b>5a</b> showed the highest binding affinity toward ER&#945; because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative <b>5d</b> maintained high binding affinity to ER&#945; and potently inhibited MCF-7 cell proliferation (IC<sub>50</sub>: 0.09 &#956;M). Docking simulation studies of compound <b>5d</b> with the ER&#945; BD revealed that the large hydrophobic moiety of compound <b>5d</b> fit well into the hydrophobic pocket of the ER&#945; LBD and that the sulfur atom of compound <b>5d</b> formed a sulfur&#8722;&#960; interaction with the amino acid residue His524 of the ER&#945; LBD. These interactions play important roles for the binding affinity of compound <b>5d</b> to the ER&#945; LBD.
topic sulfur
anticancer
estrogen
url https://www.mdpi.com/1420-3049/24/21/3966
work_keys_str_mv AT kiminoriohta designandsynthesisofnovelbreastcancertherapeuticdrugcandidatesbaseduponthehydrophobicfeedbackapproachofantiestrogens
AT asakokaise designandsynthesisofnovelbreastcancertherapeuticdrugcandidatesbaseduponthehydrophobicfeedbackapproachofantiestrogens
AT fumitaguchi designandsynthesisofnovelbreastcancertherapeuticdrugcandidatesbaseduponthehydrophobicfeedbackapproachofantiestrogens
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AT takumiogawa designandsynthesisofnovelbreastcancertherapeuticdrugcandidatesbaseduponthehydrophobicfeedbackapproachofantiestrogens
AT yasuyukiendo designandsynthesisofnovelbreastcancertherapeuticdrugcandidatesbaseduponthehydrophobicfeedbackapproachofantiestrogens
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