Abstract |
A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.
|
Authors | Cheng Shang See, Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, Sang Hyun Lee, Brian W Dymock |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 29
Issue 2
Pg. 216-219
(01 15 2019)
ISSN: 1464-3405 [Electronic] England |
PMID | 30503634
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2018 Elsevier Ltd. All rights reserved. |
Chemical References |
- A131 compound
- Antineoplastic Agents
- Indoles
- Isoquinolines
- Prodrugs
- Acrylonitrile
- Paclitaxel
|
Topics |
- Acrylonitrile
(administration & dosage, analogs & derivatives, pharmacology)
- Administration, Oral
- Animals
- Antineoplastic Agents
(administration & dosage, pharmacology)
- Colonic Neoplasms
(drug therapy)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
(drug effects)
- Drug Screening Assays, Antitumor
- Humans
- Indoles
(administration & dosage, pharmacology)
- Isoquinolines
(administration & dosage, pharmacology)
- Mice
- Molecular Structure
- Neoplasms, Experimental
(drug therapy)
- Paclitaxel
(pharmacology)
- Prodrugs
(administration & dosage, pharmacology)
- Solubility
- Structure-Activity Relationship
|