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 ERα 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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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 ERα 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 ERα 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 ERα and potently inhibited MCF-7 cell proliferation (IC<sub>50</sub>: 0.09 μM). Docking simulation studies of compound <b>5d</b> with the ERα BD revealed that the large hydrophobic moiety of compound <b>5d</b> fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound <b>5d</b> formed a sulfur−π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound <b>5d</b> to the ERα 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 ERα 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 ERα 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 ERα and potently inhibited MCF-7 cell proliferation (IC<sub>50</sub>: 0.09 μM). Docking simulation studies of compound <b>5d</b> with the ERα BD revealed that the large hydrophobic moiety of compound <b>5d</b> fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound <b>5d</b> formed a sulfur−π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound <b>5d</b> to the ERα LBD. |
topic |
sulfur anticancer estrogen |
url |
https://www.mdpi.com/1420-3049/24/21/3966 |
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