Synthesis of Cytotoxic 2,2-Difluoroderivatives of Dihydrobetulinic Acid and Allobetulin and Study of their Impact on Cancer Cells

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F15%3A33156128" target="_blank" >RIV/61989592:15110/15:33156128 - isvavai.cz</a>

Alternative codes found

RIV/68407700:21340/15:00227815 RIV/00216208:11310/15:10315850 RIV/61989592:15310/15:33156128

Result on the web

<a href="http://www.sciencedirect.com/science/article/pii/S0223523415002433" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0223523415002433</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2015.03.068" target="_blank" >10.1016/j.ejmech.2015.03.068</a>

Result language

angličtina

Original language name

Synthesis of Cytotoxic 2,2-Difluoroderivatives of Dihydrobetulinic Acid and Allobetulin and Study of their Impact on Cancer Cells

Original language description

In this article, we describe the preparation and cytotoxic properties of a small focused library of lupane and 18α-oleanane triterpenoids that contain a combination of two structural motifs known to enhance the biological activities. First, we introduced two fluorine atoms to position 2 of the skeleton. Second, we synthesized a set of hemiester prodrugs, which were intended to increase the solubility and activity. Starting from betulin, we obtained two hydroxyketones (derivatives of dihydrobetulinic acid and allobetulin) and their fluorination using DAST provided 2,2-difluoro-3-oxo-compounds as the main products. Then the 3-oxo group in each derivative was reduced by NaBH4 to obtain 3β-hydroxy compounds suitable for modifying by various hemiesters. We prepared 21 compounds, 11 of them new, their cytotoxicity was tested on T lymphoblastic leukemia CCRF-CEM cells first and the most active derivatives were selected for screening on another six tumor and two non-tumor cell lines. All of them showed selectivity against cancer lines with therapeutic index between 2 and 8. All hemiesters had activity in the same range as the free hydroxyl derivatives and they would be suitable prodrugs for future in vivo experiments. Interestingly, all hemiesters of 2,2-difluorodihydrobetulonic acid had higher activity against p53 knock-out p53-/- cancer cell line than against the non-mutated analogue. In active derivatives, the cell cycle was analyzed by flow cytometry and several compounds slowed down cell cycle progression through G0 /G1 or S-phase.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

CC - Organic chemistry

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2015

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

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Volume of the periodical

96

Issue of the periodical within the volume

MAY

Country of publishing house

FR - FRANCE

Number of pages

9

Pages from-to

482-490

UT code for WoS article

000355712500044

EID of the result in the Scopus database

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