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Featured researches published by Takashi Kawachi.


ChemMedChem | 2010

Hypoxia‐Selective Growth Inhibition of Cancer Cells by Furospinosulin‐1, a Furanosesterterpene Isolated from an Indonesian Marine Sponge

Masayoshi Arai; Takashi Kawachi; Andi Setiawan; Motomasa Kobayashi

It is generally accepted that cancer cells, which have adapted to the hypoxic environments in tumor tissues, aggravate cancer pathology by promoting tumor growth, angiogenesis, metastasis, and drug resistance. Therefore, compounds that selectively inhibit the growth of tumor cells in hypoxic environments are expected to provide new leads for promising anticancer drugs. Furospinosulin‐1, a marine‐sponge‐derived furanosesterterpene, exhibited selective antiproliferative activity against DU145 human prostate cancer cells under hypoxic conditions in concentrations ranging from 1 to 100 μM. Furospinosulin‐1 also demonstrated antitumor activity at 10–50 mg kg−1 oral administration in a mouse model inoculated with sarcoma S180 cells. Mechanistic analysis revealed that furospinosulin‐1 suppresses transcription of the insulin‐like growth factor‐2 gene (IGF‐2), which is selectively induced under hypoxic conditions through prevention of the binding of nuclear proteins to the Sp1 consensus sequence in the IGF‐2 promoter region.


Bioorganic & Medicinal Chemistry Letters | 2014

Marine spongian sesquiterpene phenols, dictyoceratin-C and smenospondiol, display hypoxia-selective growth inhibition against cancer cells.

Masayoshi Arai; Takashi Kawachi; Hiroki Sato; Andi Setiawan; Motomasa Kobayashi

In the course of our search for hypoxia-selective growth inhibitors against cancer cells, a sesquiterpene phenol, dictyoceratin-C (1), was isolated from the Indonesian marine sponge of Dactylospongia elegans under the guidance of the constructed bioassay. Dictyoceratin-C (1) inhibited proliferation of human prostate cancer DU145 cells selectively under hypoxic condition in a dose-dependent manner at the concentrations ranging from 1.0 to 10 μM. The subsequent structure-activity relationship study using nine sesquiterpene phenol/quinones (2-10), which were isolated from marine sponge, was executed. We found that smenospondiol (2) also exhibited the similar hypoxia-selective growth inhibitory activity against DU145 cells, and the para-hydroxybenzoyl ester moiety would be important for hypoxia-selective growth inhibitory activity of 1. In addition, the mechanistic analysis of dictyoceratin-C (1) revealed that the 10 μM of 1 inhibited accumulation of Hypoxia-Inducible Factor-1α under hypoxic condition.


Bioorganic & Medicinal Chemistry | 2015

Enantioselective synthesis of dictyoceratin-A (smenospondiol) and -C, hypoxia-selective growth inhibitors from marine sponge.

Yuji Sumii; Naoyuki Kotoku; Akinori Fukuda; Takashi Kawachi; Yuta Sumii; Masayoshi Arai; Motomasa Kobayashi

Total syntheses of (+)-dictyoceratin-C (1) and (+)-dictyoceratin-A (smenospondiol) (2), hypoxia-selective growth inhibitors isolated from marine sponge, were executed. The absolute stereochemistry of the each compound was determined through the enantioselective total syntheses of them. It revealed that the unnatural enantiomers of them also exhibited the hypoxia-selective growth inhibitory activity against human prostate cancer DU-145 cells.


Bioorganic & Medicinal Chemistry | 2014

Synthesis and evaluation of effective photoaffinity probe molecule of furospinosulin-1, a hypoxia-selective growth inhibitor

Naoyuki Kotoku; Chiaki Nakata; Takashi Kawachi; Takanori Sato; Xiu-Han Guo; Aoi Ito; Yuji Sumii; Masayoshi Arai; Motomasa Kobayashi

The synthesis and evaluation of a photoaffinity probe molecule for furospinosulin-1, a hypoxia-selective growth inhibitor that we identified from marine sponge, was studied. An analogue carrying an alkyne tail showed potent hypoxia-selective inhibitory activity exceeding that of the parent molecule, and exhibited in vivo anti-tumor activity following oral administration. The alkyne moiety in the analogue was also found to be a good anchoring group for the preparation of probe molecules; a photoaffinity probe molecule having an optimized spacer length was selected through the systematic synthesis of several probes and the evaluation of their hypoxia-selective growth inhibitory activity and electrophoretic mobility shift properties.


Marine Drugs | 2015

Structure-Activity Relationship and in Vivo Anti-Tumor Evaluations of Dictyoceratin-A and -C, Hypoxia-Selective Growth Inhibitors from Marine Sponge

Yuji Sumii; Naoyuki Kotoku; Akinori Fukuda; Takashi Kawachi; Masayoshi Arai; Motomasa Kobayashi

Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure–activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.


ChemBioChem | 2016

Furospinosulin-1, Marine Spongean Furanosesterterpene, Suppresses the Growth of Hypoxia-Adapted Cancer Cells by Binding to Transcriptional Regulators p54(nrb) and LEDGF/p75.

Masayoshi Arai; Takashi Kawachi; Naoyuki Kotoku; Chiaki Nakata; Haruhiko Kamada; Shin-ichi Tsunoda; Yasuo Tsutsumi; Hiroko Endo; Masahiro Inoue; Hiroki Sato; Motomasa Kobayashi

Hypoxia‐adapted cancer cells in tumors contribute to the pathological progression of cancer. Cancer research has therefore focused on the identification of molecules responsible for hypoxia adaptation in cancer cells, as well as the development of new compounds with action against hypoxia‐adapted cancer cells. The marine natural product furospinosulin‐1 (1) has displayed hypoxia‐selective growth inhibition against cultured cancer cells, and has shown in vivo anti‐tumor activity, although its precise mode of action and molecular targets remain unclear. In this study, we found that 1 is selectively effective against hypoxic regions of tumors, and that it directly binds to the transcriptional regulators p54nrb and LEDGF/p75, which have not been previously identified as mediators of hypoxia adaptation in cancer cells.


ACS Medicinal Chemistry Letters | 2012

Creation of readily accessible and orally active analogue of cortistatin a.

Naoyuki Kotoku; Yuji Sumii; Takeshi Hayashi; Satoru Tamura; Takashi Kawachi; Sho Shiomura; Masayoshi Arai; Motomasa Kobayashi

Syntheses of structurally simplified analogues of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. The analogues were designed by considering the 3-D structure of 1. Compound 30, in which the isoquinoline moiety was appended to the planar tetracyclic core structure, showed potent antiproliferative activity against human umbilical vein endothelial cells (HUVECs) together with high selectivity and also showed in vivo antiangiogenic activity and significant antitumor effect by oral administration.


Journal of Natural Medicines | 2011

Anti-angiogenic effect of triterpenoidal saponins from Polygala senega

Masayoshi Arai; Asami Hayashi; Mari Sobou; Shunsuke Ishida; Takashi Kawachi; Naoyuki Kotoku; Motomasa Kobayashi


Tetrahedron | 2011

Concise synthesis and structure–activity relationship of furospinosulin-1, a hypoxia-selective growth inhibitor from marine sponge

Naoyuki Kotoku; Shinichi Fujioka; Chiaki Nakata; Masaki Yamada; Yuji Sumii; Takashi Kawachi; Masayoshi Arai; Motomasa Kobayashi


MedChemComm | 2013

An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

Zhimin Li; Daisuke Shigeoka; Thomas R. Caulfield; Takashi Kawachi; Yushi Qiu; Takuma Kamon; Masayoshi Arai; Han W. Tun; Takehiko Yoshimitsu

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Yuji Sumii

Nagoya Institute of Technology

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