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Drug Design, Development and Therapy Volume 10, 2016 - Issue
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Original Research

5-(Bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid (BHIMHA): showing a strategy of designing drug to block lung metastasis of tumors

Taiping Gan1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China;2 Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Yuji Wang1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China;2 Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Ming Zhao1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China;2 Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China;3 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence[email protected] [email protected]
,
Jianhui Wu1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China;2 Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Jian Yang4 Ludwig Center for Cancer Genetics and Therapeutics Kimmel Cancer Center, Johns Hopkins University School of Medicine, USA
&
Shiqi Peng1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China;2 Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence[email protected] [email protected]
Pages 711-721 | Published online: 16 Feb 2016

Figures & data

Figure 1 The survey of the structural characteristics of staurosporine, BPIC, and MIAM, as well as the docking scores results in BHIMHA as a novel inhibitor of PKCα (PDB: 3IW4) capable of inhibiting metastasis of tumor toward lung, slowing tumor growth, and blocking inflammatory response.

Abbreviations: Staurosporine, (5S,6R,7R,9R)-6-methoxy-5-methyl-7-methylamino-6,7,8,9,15,16-hexahydro-5H,14H-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b, h]cyclonona [jkl]-cyclopenta [e]-asindacen-14-one; BPIC, benzyl 1-[4-hydroxy-3-(methoxycarbonyl)phenyl-9H-pyrido[3,4-b]-indole-3-carboxylate; MIAM, {2-[1-(3-methoxycar bonylmethyl-1H-indol-2-yl)-1-methylethyl]-1Hindol-3-yl}acetic acid methyl ester; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid; PDB, Protein Data Bank.
Figure 1 The survey of the structural characteristics of staurosporine, BPIC, and MIAM, as well as the docking scores results in BHIMHA as a novel inhibitor of PKCα (PDB: 3IW4) capable of inhibiting metastasis of tumor toward lung, slowing tumor growth, and blocking inflammatory response.

Figure 2 Synthesis route to BHIMHA.

Abbreviations: BHIMHAM, methyl 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoate; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid.
Figure 2 Synthesis route to BHIMHA.

Figure 3 Docking investigation of BHIMHA and staurosporine toward PKCα (PDB: 3IW4).

Notes: (A) The feature of BHIMHA in the active site of PKCα, and the amplified interactions of energy minimized BHIMHA with the amino acid residues. (B) The feature of staurosporine in the active site of PKCα, and the amplified interactions of energy minimized staurosporine with the amino acid residues.
Abbreviations: PKC, protein kinase C; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)-methyl)-2-hydroxybenzoic acid; staurosporine, (5S,6R,7R,9R)-6-methoxy-5-methyl-7-methylamino-6,7,8,9,15,16-hexahydro-5H,14H-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b, h]cyclone-na[jkl]cyclopenta[e]asindacen-14-one; PDB, Protein Data Bank.
Figure 3 Docking investigation of BHIMHA and staurosporine toward PKCα (PDB: 3IW4).

Figure 4 Effect of BHIMHA on migration and invasion of A549 cells (purple particles).

Notes: (A) Migration A549 cells in transwell chambers treated with BHIMHA for 6 hours; (B) invasion A549 cells in matrigel-coated transwell chambers treated with BHIMHA for 24 hours; (C) concentration dependence of BHIMHA inhibiting migration of A549 cells; and (D) concentration dependence of BHIMHA inhibiting invasion of A549 cells; n=3.
Abbreviations: SD, standard deviation; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)-methyl)-2-hydroxybenzoic acid.
Figure 4 Effect of BHIMHA on migration and invasion of A549 cells (purple particles).

Figure 5 In vivo BHIMHA dose dependently inhibits the metastasis of tumor toward lung.

Notes: (A) Representative photographs of LLC tumor metastasis lungs of the mice treated with NS and BHIMHA. (B) On LLC metastasis model BHIMHA inhibited metastasis of C57BL/6 mice, n=10. (C, D) Western blot assay showing the effect of BHIMHA on the expression of PKCα from A549 cells, n=3.
Abbreviations: NS, normal saline; LLC, Lewis lung carcinoma; PKCα, protein kinase Cα; BHIMHA, 5-(bis-(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid; staurosporine, (5S,6R,7R,9R)-6-methoxy-5-methyl-7-methylamino-6,7,8,9,15,16-hexahydro-5H,14H-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b, h]cyclonona[jkl] cyclopenta[e]asindacen-14-one.
Figure 5 In vivo BHIMHA dose dependently inhibits the metastasis of tumor toward lung.

Figure 6 In vivo oral BHIMHA dose dependently inhibits the growth of the primary tumor of LLC planted C57BL/6 mice (n=10).

Abbreviations: NS, normal saline; LLC, Lewis lung carcinoma; SD, standard deviation; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid.
Figure 6 In vivo oral BHIMHA dose dependently inhibits the growth of the primary tumor of LLC planted C57BL/6 mice (n=10).

Figure 7 In vivo activities of BHIMHA, Dox and NS in slowing tumor growth of S180 mice, n=12.

Abbreviations: NS, normal saline; Dox, doxorubicin; SD, standard deviation; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid.
Figure 7 In vivo activities of BHIMHA, Dox and NS in slowing tumor growth of S180 mice, n=12.

Figure 8 (A) In vivo activity of BHIMHA inhibiting xylene-induced ear edema of ICR mice, n=10; (B, C) effect of BHIMHA on the expression of NF-κB from A549 cells, n=3.

Abbreviations: NS, normal saline; NF-κB, nuclear factor-κB; SD, standard deviation; BHIMHA, 5-(bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid; PDTC, ammonium pyrrolidinedithiocarbamate; Aspirin, acetylsalicylic acid.
Figure 8 (A) In vivo activity of BHIMHA inhibiting xylene-induced ear edema of ICR mice, n=10; (B, C) effect of BHIMHA on the expression of NF-κB from A549 cells, n=3.

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