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Morpholinylanthracyclines: cytotoxicity and antitumor activity of differently modified derivatives
M Ripamonti1, L Capolongo, G Melegaro
1Pharmacia Research Center, Oncology Department, Milano, Merviano, Italy.
Abstract:
The relationship between different chemical modifications on morpholinylanthracyclines and their ability to overcome multidrug resistance (MDR) has been evaluated testing all compounds in vitro on LoVo and LoVo/DX human colon adenocarcinoma cells and in vivo disseminated P388 and P388/DX murine leukemias. Results obtained led us to the following conclusions: 1) the insertion of the morpholinyl or the methoxymorpholinyl group on position 3' of the sugar moiety confers the ability to overcome MDR in vitro and in vivo; conversely, 4' morpholinyl compounds are effective on MDR cells only in vitro and result inactive in vivo on DX-resistant leukemia; 2) all chemical modifications performed on 3' morpholinyl or methoxymorpholinyl derivatives, that is substitutions on the aglycone or on position 2 of the morpholino ring, do not interfere with the activity of the compounds: all derivatives present in fact the same efficacy on sensitive and resistant models. It is concluded that position 3' in the sugar moiety plays a crucial role in the ability of morpholinyl-anthracyclines to overcome MDR.
Insights
Morpholinyl-anthracyclines modified at the 3' sugar position effectively overcome multidrug resistance (MDR) in cancer cells, both in vitro and in vivo. Modifications elsewhere do not impact this crucial MDR-overcoming ability.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Research
Background:
- Multidrug resistance (MDR) significantly limits the efficacy of anthracycline chemotherapy.
- Developing novel anthracycline derivatives is crucial to overcome MDR in cancer treatment.
Purpose of the Study:
- To investigate the structure-activity relationship of morpholinyl-anthracyclines concerning their ability to overcome MDR.
- To identify key structural modifications responsible for MDR circumvention.
Main Methods:
- In vitro testing of compounds on LoVo and LoVo/DX human colon adenocarcinoma cells.
- In vivo evaluation using disseminated P388 and P388/DX murine leukemia models.
Main Results:
- Morpholinyl or methoxymorpholinyl groups at the 3' sugar position confer MDR-overcoming ability both in vitro and in vivo.
- 4' morpholinyl compounds were effective only in vitro against MDR cells and inactive in vivo.
- Modifications on the aglycone or morpholino ring of 3' derivatives did not alter their efficacy on sensitive or resistant models.
Conclusions:
- Position 3' of the sugar moiety is critical for morpholinyl-anthracyclines to overcome MDR.
- Specific modifications at the 3' position are key to developing effective MDR-circumventing anthracycline therapies.