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Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid
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Titel: |
Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid |
In: | ChemMedChem, 12, 2017, 5, S. 390-398 |
veröffentlicht: |
Wiley
|
Umfang: | 390-398 |
ISSN: |
1860-7179 1860-7187 |
DOI: | 10.1002/cmdc.201600626 |
Zusammenfassung: | <jats:title>Abstract</jats:title><jats:p>A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3‐oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N‐substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non‐cancer fibroblasts. 2‐Bromoallobetulone (<jats:bold>2 b</jats:bold>) methyl 2‐bromobetulonate (<jats:bold>3 b</jats:bold>), 2‐bromooleanonic acid (<jats:bold>5 b</jats:bold>), and 2‐thiocyanooleanonic acid (<jats:bold>5 c</jats:bold>) were best, with IC<jats:sub>50</jats:sub> values less than 10 μ<jats:sc>m</jats:sc> against CCRF‐CEM cells (e.g., <jats:bold>3 b</jats:bold>: IC<jats:sub>50</jats:sub>=2.9 μ<jats:sc>m</jats:sc>) as well as 2′‐(diethylamino)olean‐12(13)‐eno[2,3‐<jats:italic>d</jats:italic>]thiazole‐28‐oic acid (<jats:bold>5 f</jats:bold>, IC<jats:sub>50</jats:sub>=9.7 μ<jats:sc>m</jats:sc>) and 2′‐(<jats:italic>N</jats:italic>‐methylpiperazino)olean‐12(13)‐eno[2,3‐<jats:italic>d</jats:italic>]thiazole‐28‐oic acid (<jats:bold>5 k</jats:bold>, IC<jats:sub>50</jats:sub>=11.4 μ<jats:sc>m</jats:sc>). Compound <jats:bold>5 c</jats:bold> leads to the accumulation of cells in the G<jats:sub>2</jats:sub> phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1×IC<jats:sub>50</jats:sub>. The G<jats:sub>2</jats:sub>/M cell‐cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound <jats:bold>5 c</jats:bold> is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2‐bromobetulonate (<jats:bold>3 b</jats:bold>) and methyl 2‐thiocyanometulonate (<jats:bold>3 c</jats:bold>) were found to inhibit nucleic acid synthesis only at 5×IC<jats:sub>50</jats:sub>. We assume that in <jats:bold>3 b</jats:bold> and <jats:bold>3 c</jats:bold> (unlike in <jats:bold>5 c</jats:bold>), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1×IC<jats:sub>50</jats:sub> or lower concentration.</jats:p> |
Format: | E-Article |
Quelle: | Wiley (CrossRef) |
Sprache: | Englisch |