Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents
スポンサーリンク
概要
- 論文の詳細を見る
Certain antimicrotubule agents displaying colchicine-like tubulin-depolymerizing activity can act as both cytotoxic and vascular-disrupting agents (VDAs). VDAs constitute a new class of anticancer drugs and are currently in clinical trials. We have developed a VDA clinical candidate (phase II) diketopiperazine (DKP)-type antimicrotubule agent called plinabulin (7) derived from the natural DKP phenylahistin (5), which displays colchicine-like tubulin-depolymerizing activity. To develop more potent antimicrotubule DKP derivatives, we performed an intensive structure–activity relationship study examining the phenyl group of compound 7. This study identified more potent DKP derivatives (2,5-difluoro derivatives [29] and benzophenone derivatives [36]) with vascular-disrupting activities. The benzophenone moiety of compound 36 was further modified to yield the most potent cytotoxic derivative yet discovered, the 4-fluorobenzophenone derivative 38m, which inhibited the growth of HT-29 cells in vitro at subnanomolar levels. As both VDAs and cytotoxic agents, these potent DKP derivatives are valuable second-generation drug candidates. The chemical biology of plinabulin was examined by designing and synthesizing biotin-tagged photoaffinity probes 40–42 that could be used to indicate the binding mode of compound 7 with tubulin. A tubulin photoaffinity labeling study suggested that compound 7 binds at the interface between the α- and β-tubulins near the colchicine-binding site and not inside the colchicine-binding cavity. A water-soluble prodrug of the poorly water-soluble 7 was next designed in an effort to improve the pharmacokinetics and chemotherapeutic indices. The lead compound 56 revealed high water solubility and a half-life profile appropriate for an injected drug.
著者
-
Yakushiji Fumika
Department Of Medicinal Chemistry School Of Pharmacy Tokyo University Of Pharmacy And Life Sciences
-
Hayashi Yoshio
Department Of Chemistry Faculty Of Science Kanazawa University
-
Yamazaki-Nakamura Yuri
Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy
-
Yakushiji Fumika
Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy
-
Hayashi Yoshio
Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy
関連論文
- Development of New Photoresponsive Paclitaxel Prodrug
- Phototaxel : Development of First Photoresponsive Prodrug of Paclitaxel via Modification of Phenylisoserine Moiety
- "Click Peptide" : the "O-Acyl Isopeptide Method" for Peptide Synthesis and Development of Chemical Biology-Oriented Aβ Analogues
- "Click Peptide" Based on the "O-Acyl Isopeptide Method" : Development of Chemical Biology-Oriented Alzheimer's Disease-Related Aβ1-42 Analogues
- Design and Synthesis of Dipeptide-type HIV-1 Protease Inhibitors with High Antiviral Activity
- Controlled Drug Release : Design and Application of New Water-soluble Prodrugs
- Spontaneously Regenerable Prodrug : Design and Synthesis of Water-soluble Prodrugs of HIV Protease Inhibitors
- Design of Double-Drug-Type Anti-HIV Agents
- Racemization-Free Segment Condensation Based on Isopeptide Method : An Efficient Preparation of Peptides on Solid Support
- The Synthesis of Bioactive Peptides Based on O-Acyl Isopeptide Method : Application of O-Acyl Isodipeptide Units
- Development of Racemization-Free "O-Acyl Isopeptide Method" Utilizing the "O-Acyl Isodipeptide Unit"
- P-262 "O-ACYL ISOPEPTIDE METHOD" FOR THE EFFICIENT SYNTHESIS OF DIFFICULT SEQUENSE-CONTAINING PEPTIDES : UTILIZATION OF "O-ACYL ISODIPEPTIDE UNIT"
- Conversion of Polymer-Bound Dipeptide to Evans-Type Chiral Auxiliary : A New Tool for Efficient Solid-Phase Asymmetric Reactions
- Revised Japanese criteria for Sjogren's syndrome (1999) : availability and validity
- FEM-Based Electromagnetic Wave Simulator Running on Some Platforms by Use of Java and a Commercial Tool(Analytical and Simulation Methods for Electromagnetic Wave Problems)
- FEM-Based Electromagnetic Wave Simulator Running on Some Platforms by Use of Java and a Commercial Tool
- Development of Spontaneously Regenerable Water-Soluble Prodrugs Based on the Peptide Chemistry : Importance of Drug Release Time for the Improvement of Gastrointestinal Absorption
- Metastatic Prostate Carcinoma to the Mandible : Report of a case
- Malignant Melanoma in situ of the Lower Lip
- Novel BACE1 Inhibitors : Design Approach Focused on Inhibitor's Conformer
- Structure-Activity Relationship Study of BACE1 Inhibitors Containing Chelidonamide
- Oligoarginine-Based Prodrugs with Self-Cleavable Spacers for Caco-2 Cell Permeation
- Synthesis and Activity of Tetrapeptidic Human T-cell Leukemia Virus Type I Protease Inhibitors Possessing Different P_1'- and P_3-cap Moieties
- Design of BACE1 Inhibitors : Replacing the P_1' Residue with Non-Acidic Moiety
- Design and Synthesis of Conformationally Constrained Dimerization Inhibitors of HIV-1 Protease
- Synthesis of Negamycin and Its Derivatives as Potential Therapeutic Agents for Duchenne Muscular Dystrophy
- Phenylthionorstatine as a Transition-State Mimic in BACE1 Inhibitors
- Tripeptide Mimetics with Potent Inhibitory Activity against Malarial Aspartic Protease Plasmepsin II
- P-296 DEVELOPMENT OF RESIN SUPPORTED EVANS-TYPE CHIRAL AUXILIARY FOR SOLID-PHASE ASYMMETRIC REACTION
- Modification of P4 Position in β-secretase (BACE1) Inhibitors Containing Phenylnorstatine
- Design of β-Secretase (BACE1) Inhibitors with Carboxylic Acid Bioisosteres
- Convenient and Regioselective Syntheses of 3, 4-Disubsutituted Δ^3-Pyrrolin-2-one Derivatives Starting from 2-Tosyl-3, 4-Disubstituted Pyrroles
- Evaluation of Peptidomimetic HTLV-I Protease Inhibitors Containing Hydroxymethylcarbonyl as a Transition-State Isostere
- O-N Intramolecular Acyloxy Migration Reaction : from the Prodrug Strategy to the Migration of Protective Groups in Amino Acids
- "Click Peptide" Based on the "O-Acyl Isopeptide Method" : an Efficient Preparation of Amyloid β Peptide 1-42 Mutants
- Design and Synthesis of β-Secretase Inhibitors Containing Hydroxymethylcarbonyl Isostere as a Transition State Mimic
- Three-dimensional Quantitative Structure-Activity Relationship Analysis of RGD Mimetics as Fibrinogen Receptor Antagonists
- Chemical Synthesis of 71-meric Neuregulin 1-β1
- The Rate of Cell Growth Is Regulated by Purine Biosynthesis via ATP Production and G1 to S Phase Transition
- Mechanisms of Transfer into SCID Mice Reconstituted with Tissueinfiltrating Cells from Murine Model for Sjogren's Syndrome
- Large Cell Undifferentiated Carcinoma of the Parotid Gland Containing Malignant Oncocytic Change
- Click Peptide by Use of the O-Acyl Isopeptide Method : Production of Amyloid β Peptide from Water-Soluble Analogue
- "O-Acyl Isopeptide Method" for the Synthesis of Difficult Sequence-Containing Peptides : Application to the Synthesis of Amyloid β Peptide (Aβ) 1-42
- Effect of the Phenyl Ring Modification on the Antitumor Activity of Anti-Microtubule Agent Dehydrophenylahistin
- Uptake Mechanisms of FITC-Oligoarginine Conjugates in HeLa Cells
- Design and Synthesis of Oligoarginine-Fluorescein Conjugates Possessing Novel Self-Cleavable Spacers as a Model for Effective Intestinal Absorption
- Efficient Total Synthesis of (+)-Negamycin and Its Derivatives
- Small Peptide-based Medicinal Chemistry for Intractable Disease
- A Synthetic Method for Monodehydro-Cyclic-Dipeptides toward Natural Product Synthesis
- New Aspects of Potent Anti-Microtubule Agents Phenylahistin and Tubulin Photoaffinity Labeling
- P-518 DEVELOPMENT OF POTENT ANTI-MICROTUBULE AGENTS BASED ON NATURAL DIKETOPIPERAZINE PHENYLAHISTIN AND TUBULIN PHOTOAFFINITY LABELING
- Development of a New Synthetic Method for Monodehydro-2,5-diketopiperazines
- Synthetic Study of Anti-microtubule Diketopiperazines : Phenylahistin and Aurantiamine
- Cytokines, Adhesion Molecules, and Immune Deviation in Autoimmune Salivary Gland Disease
- Design and Synthesis of Highly Active β-Secretase (BACE1) inhibitors, KMI-420 and KMI-429, with Enhanced Chemical Stability
- Evaluation of Peptidomimetic Inhibitors against Malarial Protease Plasmepsin
- Dipeptide-Type Inhibitors Targeting Plasmepsins from Plasmodium Falciparum
- Analysis of Side Reaction in the Amide Bond Formation with an α-Hydroxy-β-amino Acid as an Acyl Componemt
- Substrate Transition-State Analogue Inhibitors of Plasmepsin II as Antimalarial Drugs
- An Approach for Peptidic Aspartic Protease Inhibitors Using Ala-containing Oligopeptides Independent of the Substrate Sequence
- Development of a New Synthetic Method for L-Tetrahydrofuranylglycine and Its Application for Substrate-based HIV-1 Protease Inhibitors
- Carcinoma in Pleomorphic Adenoma of the Tongue : Report of a case
- O-N Intramolecular Acyl and Acyloxy Migration Reaction in the Development of Water-Soluble Prodrugs of Taxoids
- A Novel Method for the Synthesis of Difficult Sequence-Containing Peptides via O-Acyl Isopeptides : The Use of O-N Intramolecular Acyl Migration Reaction
- Development of New Water-Soluble Prodrugs Based on Intramolecular Nucleophilic Reactions in Peptide Chemistry
- Delivery of small interfering RNA with a synthetic collagen poly (Pro-Hyp-Gly) for gene silencing in vitro and in vivo
- Epitope mapping of anti-α-fodrin antibody in a case of early-onset multiple sclerosis
- Atelocollagen-mediated systemic administration of myostatin-targeting siRNA improves muscular atrophy in caveolin-3-deficient mice
- Crucial Role of Tissue-specific Apoptosis on the Development of Primary Sjogren's Syndrome
- Development of a Solid-supported Biotinylation Reagent for the Efficient Biotin Labeling to the SH group of Peptides and Small Molecules
- Structure Activity Relationship Study of SARS Coronavirus 3CL Protease Inhibitors with an Electrophilic Aryl Ketone Structure
- Synthesis and Biological Evaluation of Dipeptidic Antibiotics (+)-Negamycin and Its Derivatives for Development of Duchenne Muscular Dystrophy Chemotherapy
- Development of Chemical Probes towards the Elucidation of Binding Mechanism of Plinabulin, a Cyclicdipeptide Based Anti-microtubule Agent
- Unique cell membrane expression of topoisomerase-II alpha as a useful diagnostic marker of liposarcoma
- Crucial Roles of NF-κB for T Cell Activation
- Design, Synthesis and Evalution of Tripeptidomimetics with Arylketone as Inhibitors of SARS-CoV 3CL Protease
- Development of (+)-Negamycin Derivatives with Potent Readthrough Activity for Duchenne Muscular Dystrophy Chemotherapy
- Regulation of T cell activation in Sjogren's syndrome
- Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents
- Toxicity of formaldehyde in experimental animals. Concentrations of the chemical in the elution from dishes of formaldehyde resin in some vegetables.:CONCENTRATIONS OF THE CHEMICAL IN THE ELUTION FROM DISHES OF FORMALDEHYDE RESIN IN SOME VEGETABLES
- Structure Activity Relationship Study of Dipeptide Antibiotic (+)-Negamycin for the Potent Readthrough Promoting Activity