Novel Di-Tertiary-Butyl Phenylhydrazones as Dual Cyclooxygenase-2/5- Lipoxygenase Inhibitors: Synthesis, COX/LOX Inhibition, Molecular Modeling, and Insights into Their Cytotoxicities
Although dual inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) enzymes is highly effective than targeting COX or LOX alone, there are only a few reports of examining such compounds in case of colorectal cancers (CRC). In the present work we report that the novel di-tert-butyl phenol-based dual inhibitors DTPSAL, DTPBHZ, DTPINH, and DTPNHZ exhibit significant cytotoxicity against human CRC cell lines. Molecular docking studies revealed a good fit of these compounds in the COX-2 and 5-LOX protein cavities. The inhibitors show significant inhibition of COX-2 and 5-LOX activities and are effective against a panel of human colon cancer cell lines including HCA-7, HT-29, SW480 and intestinal Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressing colon cancer cells, through inhibition of the Hyaluronan/CD44v6 cell survival pathway. Western blot analysis and qRT-PCR analyses indicated that the di-tert-butyl phenol-based dual inhibitors reduce the expression of COX-2, 5-LOX, and CD44v6 in human colon cancer HCA-7 cells, while the combination of CD44v6shRNA and DTPSAL has an additional inhibitory effect on CD44v6 mRNA expression. The synergistic inhibitory effect of Celecoxib and Licofelone on CD44v6 mRNA expression suggests that the present dual inhibitors down-regulate cyclooxygenase and lipoxygenase enzymes through CD44v6. The compounds also exhibited enhanced antiproliferative potency compared to standard dual COX/LOX inhibitor, viz. Licofelone. Importantly, the HA/CD44v6 antagonist CD44v6shRNA in combination with synthetic compounds had a sensitizing effect on the cancer cells which enhanced their antiproliferative potency, a finding which is crucial for the anti-proliferative potency of the novel synthetic di-tert-butyl phenol based dual COX-LOX inhibitors in colon cancer cells.
S. Ghatak and A. C. Vyas and S. K. Misra and P. E. O'Brien and A. Zambre and V. M. Fresco and R. R. Markwald and K. V. Swamy and Z. Afrasiabi Navan and A. Choudhury and M. B. Khetmalas and S. B. Padhyé, "Novel Di-Tertiary-Butyl Phenylhydrazones as Dual Cyclooxygenase-2/5- Lipoxygenase Inhibitors: Synthesis, COX/LOX Inhibition, Molecular Modeling, and Insights into Their Cytotoxicities," Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 1, pp. 317-324, Elsevier, Jan 2014.
The definitive version is available at https://doi.org/10.1016/j.bmcl.2013.11.015
Keywords and Phrases
Antineoplastic Agent; Arachidonate 5 Lipoxygenase; CD44v6 Antigen; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitor; Darbufelone; Di Tert Butyl Phenylhydrazone; Hyaluronic Acid Derivative; Licofelone; Lipoxygenase Inhibitor; Messenger RNA; Phenylhydrazone Derivative; Short Hairpin RNA; Synthetase; Unclassified Drug; Antineoplastic Agent; CD44v6 Antigen; Celecoxib; Cyclooxygenase 2 Inhibitor; Darbufelone; Licofelone; Lipoxygenase Inhibitor; Phenylhydrazone Derivative; Antiproliferative Activity; Article; Cancer Cell; Cell Survival; Colorectal Cancer; Controlled Study; Drug Cytotoxicity; Drug Synthesis; Enzyme Activity; Enzyme Inhibition; Gene Expression; Human; Human Cell; Molecular Docking; Molecular Model; Protein Expression; Reverse Transcription Polymerase Chain Reaction; Western Blotting; Antigen Expression; Antineoplastic Activity; Article; Cell Proliferation; Drug Potentiation; Enzyme Linked Immunosorbent Assay; HT 29 Cell Line; IC50; MTT Assay; Stereospecificity; Upregulation; Antitumor Agents; CD44v6; Colon Cancer; Cytotoxicity; Di-tert Butyl Phenols; Dual COX-LOX Inhibitors; Hyaluronan; Molecular Modeling; Antineoplastic Agents; Arachidonate 5-Lipoxygenase; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Hydrazones; Lipoxygenase Inhibitors; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Antitumor Agents; CD44v6; Colon Cancer; Cytotoxicity; Di-tert Butyl Phenols; Dual COX-LOX Inhibitors; Hyaluronan; Molecular Modeling
International Standard Serial Number (ISSN)
Article - Journal
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