Synthesis and anticancer activity of chalcone-pyrrolobenzodiazepine conjugates linked via 1,2,3-triazole ring side-armed with alkane spacers

Aiming to develop multitarget drugs for the anticancer treatment, a new class of chalcone-pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) conjugates linked through a 1,2,3-triazole moiety containing alkane spacers has been designed and synthesized. Combining these two core pharmacophore structures with modifications at A-C8/C-C2-position of PBD ring system yielded analogs with improved efficacy and have shown promising in vitro anticancer activity ranging from <0.1–2.92 μM. These PBD-conjugates caused G1 cell cycle arrest with effect on G1 cell cycle regulatory proteins such as Cyclin D1 and Cdk4. These conjugates also exhibited inhibitory effect on NF-kB, Bcl-XL proteins that play a vital role in breast cancer cell proliferation. These findings suggest that one of the compound 4d among this series is most effective and has potential for detailed investigations.

Graphical abstractA series of new chalcone-pyrrolobenzodiazepine conjugates connected through a 1,2,3-triazole containing alkane spacers has been synthesized and evaluated for their in vitro anticancer activity (<0.1–2.92 μM) on selected human cancer cell lines.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► New chalcone linked PBD conjugates with significant anticancer activity. ► ‘Click’ chemistry protocol has been utilized. G1 cell cycle arrest in MCF-7 cell line. ► Down regulation of cyclin D1 and Cdk4 have observed. ► Down regulation of NF-kB, Bcl-xL and Bcl2 were also observed.