Abstract
3-(Aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives were synthesized by the structural modification of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) that incorporated homologue-alkyl linkers, without or with an extended 3- amino-1,2,4-benzotriazine-1-oxide moiety at the 3-position of the TPZ. According to sequential evaluation of preferentially normoxic and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds exhibited hypoxic cytotoxicity greater than or comparable to that of TPZ. Among them, compounds 9a and 9b more powerfully inhibited the proliferation of MCF-7, NCI-H460 and HCT-116 in hypoxia than did TPZ. The representative of 3-(aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives, 9a exhibited greater hypoxic cytotoxicity than TPZ, mediated by cell cycle arrest. The induction of DNA damage, the activation of caspase 3/7 and cleaved poly(ADP-ribose) polymerase-related apoptosis, which were detected in HCT-116 cells in both normoxia and hypoxia. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts that were exposed to the selected 7b, 8g, 9a and 9b exhibited 80-90% inhibition of tube formation at 20 µM, whereas TPZ exhibited approximately 50% inhibition of tube formation at 20 µM. At 2 µM, 9a and 9b significantly reduced the areas, lengths, paths and joints of tube formation by 70-80% and 45-50%, respectively. These results reveal that most of synthesized TPZ derivatives in this study exhibited more potent anti-angiogenesis than TPZ.
Keywords: Anti-angiogensis, apoptosis, 3-amino-1, 2, 4-benzotriazine-1, 4-dioxide (tirapazamine), bioreductive agent, hypoxic cytotoxin.
Anti-Cancer Agents in Medicinal Chemistry
Title:Synthesis, Preferentially Hypoxic Apoptosis and Anti-Angiogenic Activity of 3- Amino-1,2,4-Benzotriazine-1,4-Dioxide Bearing Alkyl Linkers with a 3-Amino-1,2,4- Benzotriazine-1-Oxide Moiety
Volume: 14 Issue: 10
Author(s): Chun-I Lee, Chien-Ming Huang, Wen-Hsin Huang and An-Rong Lee
Affiliation:
Keywords: Anti-angiogensis, apoptosis, 3-amino-1, 2, 4-benzotriazine-1, 4-dioxide (tirapazamine), bioreductive agent, hypoxic cytotoxin.
Abstract: 3-(Aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives were synthesized by the structural modification of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) that incorporated homologue-alkyl linkers, without or with an extended 3- amino-1,2,4-benzotriazine-1-oxide moiety at the 3-position of the TPZ. According to sequential evaluation of preferentially normoxic and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds exhibited hypoxic cytotoxicity greater than or comparable to that of TPZ. Among them, compounds 9a and 9b more powerfully inhibited the proliferation of MCF-7, NCI-H460 and HCT-116 in hypoxia than did TPZ. The representative of 3-(aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives, 9a exhibited greater hypoxic cytotoxicity than TPZ, mediated by cell cycle arrest. The induction of DNA damage, the activation of caspase 3/7 and cleaved poly(ADP-ribose) polymerase-related apoptosis, which were detected in HCT-116 cells in both normoxia and hypoxia. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts that were exposed to the selected 7b, 8g, 9a and 9b exhibited 80-90% inhibition of tube formation at 20 µM, whereas TPZ exhibited approximately 50% inhibition of tube formation at 20 µM. At 2 µM, 9a and 9b significantly reduced the areas, lengths, paths and joints of tube formation by 70-80% and 45-50%, respectively. These results reveal that most of synthesized TPZ derivatives in this study exhibited more potent anti-angiogenesis than TPZ.
Export Options
About this article
Cite this article as:
Lee Chun-I, Huang Chien-Ming, Huang Wen-Hsin and Lee An-Rong, Synthesis, Preferentially Hypoxic Apoptosis and Anti-Angiogenic Activity of 3- Amino-1,2,4-Benzotriazine-1,4-Dioxide Bearing Alkyl Linkers with a 3-Amino-1,2,4- Benzotriazine-1-Oxide Moiety, Anti-Cancer Agents in Medicinal Chemistry 2014; 14 (10) . https://dx.doi.org/10.2174/1871520614666141014130554
DOI https://dx.doi.org/10.2174/1871520614666141014130554 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Radiation Oncology and Molecular-Targeted Therapy for EGFR and its Signal Transduction Pathways: Molecular Basis and Clinical Application for Improvement of Radiotherapeutic Outcomes
Current Signal Transduction Therapy The Role of Bevacizumab in Advanced Epithelial Ovarian Cancer
Current Pharmaceutical Design Withdrawal Notice: The Recent Advancement in the Field of Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) for Aiming Breast Cancer
Current Drug Metabolism Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review
Current Cancer Drug Targets Peripheral TRPV1 Receptors As Targets for Drug Development: New Molecules and Mechanisms
Current Pharmaceutical Design Ganglioside GM3 and Its Role in Cancer
Current Medicinal Chemistry Melatonin and Synthetic Melatoninergic Agonists in Psychiatric and Age-associated Disorders: Successful and Unsuccessful Approaches
Current Pharmaceutical Design The Role of Apoptosis in Cancer Development and Treatment: Focusing on the Development and Treatment of Hematologic Malignancies
Current Pharmaceutical Design Sphingolipid Modulation: A Strategy for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Topical Delivery of Drugs for the Effective Treatment of Fungal Infections of Skin
Current Pharmaceutical Design Small-Molecule Inhibitors of Bcl-2 Family Proteins as Therapeutic Agents in Cancer
Recent Patents on Anti-Cancer Drug Discovery Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy
Current Medicinal Chemistry The Tumor Stroma as Mediator of Drug Resistance - A Potential Target to Improve Cancer Therapy?
Current Pharmaceutical Biotechnology Sensoring Strategies Using Quantum Dots: A Critical View
Current Organic Chemistry Synthesis and Evaluation of A New Series of Thiazole Derivatives as Potential Antitumor Agents and MMP Inhibitors
Anti-Cancer Agents in Medicinal Chemistry KSP Inhibitors as Antimitotic Agents
Current Topics in Medicinal Chemistry Small Molecular Inhibitors Targeting Chromatin Regulating Proteins for Cancer
Current Protein & Peptide Science Anesthetics Mechanisms: A Review of Putative Target Proteins at the Cellular and Molecular Level
Current Drug Targets Anti-inflammatory Phytochemicals for Chemoprevention of Colon Cancer
Current Cancer Drug Targets A Family of Pleiotropically Acting MicroRNAs in Cancer Progression, miR-200: Potential Cancer Therapeutic Targets
Current Pharmaceutical Design