Synthesis and preliminary anticancer evaluation of new triazole bisphosphonate-based isoprenoid biosynthesis inhibitors

The synthesis of a new set of triazole bisphosphonates 8a-d and 9a-d presenting an alkyl or phenyl substituent at the C-4 or C-5 position of the triazole ring is described. These compounds have been evaluated for their antiproliferative activity against MIA PaCa-2 (pancreas), MDA-MB-231 (breast) and A549 (lung) human tumor cell lines. 4-hexyl- and 4-octyltriazole bisphosphonates 8b-c both displayed remarkable antiproliferative activities with IC50 values in the micromolar range (0.75-2.4 mu M) and were approximately 4 to 12-fold more potent than zoledronate. Moreover, compound 8b inhibits geranylgeranyl pyrophosphate biosynthesis in MIA PaCa-2 cells which ultimately led to tumor cells death. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A new series of triazole bisphosphonates with alkyl or phenyl substituents exhibited strong antiproliferative activity against human tumor cell lines, particularly the 4-hexyl and 4-octyltriazole bisphosphonates which were significantly more potent than zoledronate.Compound 8b was found to inhibit geranylgeranyl pyrophosphate biosynthesis in MIA PaCa-2 cells leading to tumor cell death.