Design and synthesis of novel structures with anti-tumor effects: Targeting telomere G-quadruplex and hTERT.

The telomeric G-quadruplex (G4) along with the telomerase catalytic subunit hTERT are crucial in the extension of telomeres. Tumor cells can establish replicative immortality by activating the telomere-maintenance mechanism (TMM).Small molecule ligands can limit cancer telomere lengthening by by targeting at G4 and hTERT. The 144 structures were designed by summarising the common structure-activity relationship of G4 stabilisers and hTERT inhibitors.Molecular docking and mtQSAR activity prediction experiments finally identified a16 and a35 as the optimal structures. Subsequently their derivative compounds b1-b6 were synthesised,with b4 exhibiting the most pronounced inhibitory effect on tumour cells. The ability of b4 to distinguish single-stranded DNA, double-stranded DNA and telomere G4 was verified by fluorescence experiment, and the stable combination of b4 and hTERT was verified by molecular dynamics simulation. This suggests that the structural design of targeting G4 and hTERT is reasonable and has anti-tumor potential.