Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy
| Autor: | Ho H. Lee, Sunali Mehta, H. D. Sarath Liyanage, Sally Y. Bai, Frederik B. Pruijn, Moana Tercel, Jean-Jacques Youte Tendoung |
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| Rok vydání: | 2017 |
| Předmět: |
Indoles
Stereochemistry medicine.medical_treatment Mice Nude Antineoplastic Agents Pharmacology 01 natural sciences Duocarmycins Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Morpholine Drug Discovery medicine Side chain Animals Humans Ovarian Neoplasms Chemotherapy 010405 organic chemistry Chemistry Ovary Nitro Compounds Combined Modality Therapy Cell Hypoxia Pyrrolidinones In vitro Gemcitabine 0104 chemical sciences Docetaxel 030220 oncology & carcinogenesis Nitro Molecular Medicine Female Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 60:5834-5856 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00563 |
| Popis: | A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pKa 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of γ irradiation 50 at 42 μmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment we... |
| Databáze: | OpenAIRE |
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