An unexpected Dimroth rearrangement leading to annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines with potent antitumor activity

• An unusual Dimroth rearrangement led to new thienotriazolopyrimidine derivatives.
• The biological screenings showed their strong antiproliferative activity.
• The most active compound showed low toxicity and high potency in vivo.

An unusual Dimroth rearrangement occurring in the reaction leading to annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core allowed the isolation of the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. By decorating the linear isomer with the same chains that improved the biological activity of the angular isomers, new annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines were designed and synthesized. They were selected by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited strong antiproliferative activity up to nanomolar concentration. In vivo screenings of the most active compound, the N-[2-(1H-imidazol-4-yl)ethyl]-4-(3-phenyl-10-oxo-4,10-dihydrobenzothieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidin-4-yl)butanamide, showed its low toxicity and high potency.

Dimroth rearrangement occurred in the synthesis of annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core, giving the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. Derivatives of this skeleton possess potent antitumor activity.Figure optionsDownload as PowerPoint slide