Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides

Qingfeng Li; Elisabetta Groaz; Leentje Persoons; Dirk Daelemans; Piet Herdewijn

doi:10.1021/acsmedchemlett.0c00269

Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides

ACS Med Chem Lett. 2020 Jul 9;11(8):1605-1610. doi: 10.1021/acsmedchemlett.0c00269. eCollection 2020 Aug 13.

Authors

Qingfeng Li¹, Elisabetta Groaz¹, Leentje Persoons², Dirk Daelemans², Piet Herdewijn¹

Affiliations

¹ Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1041, 3000 Leuven, Belgium.
² Laboratory of Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1043, 3000 Leuven, Belgium.

Abstract

A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold with various alkynyl and aryl groups starting from a common 7-iodo-pyrrolotriazine C-ribonucleoside intermediate. Analogues bearing a 7-cyclopropyl-, 7-propyl-, and 7-butylacetylene moiety displayed potent cytotoxic activity, with the latest being the most selective of this series toward cancer cells. Further insights revealed that such C-nucleosides could exert their antiproliferative action by causing dose-dependent DNA damage.