title: Synthesis of new indole-based bisphosphonates and evaluation of their chelating ability in PE/CA-PJ15 cells.
abstract: Bisphosphonates are the most important class of antiresorptive agents used against osteoclast-mediated bone loss, and, more recently, in oncology. These compounds have high affinity for calcium ions (Ca(2+)) and therefore target bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. They are extensively used in healthcare, however they are affected by severe side effects; pharmacological properties of bisphosphonates depend on their molecular structure, which is frequently the cause of poor intestinal adsorption and low distribution. In this work we synthesized six novel bisphosphonate compounds having a variably substituted indole moiety to evaluate their extra- and intracellular calcium chelating ability in PE/CA-PJ15 cells. Preliminary in silico and in vitro ADME studies were also performed and the results suggested that the indole moiety plays an important role in cell permeability and metabolism properties.
authors: Department of Agricultural, Food and Environment Science (Unit Research of Biochemistry and Molecular Biology), University of Perugia, via Del Giochetto, 06125 Perugia, Italy.
authors: Carlo A
authors: CA
authors: Palmerini
authors: Department of Agricultural, Food and Environment Science (Unit Research of Biochemistry and Molecular Biology), University of Perugia, via Del Giochetto, 06125 Perugia, Italy.
authors: Francesco
authors: F
authors: Tartacca
authors: Department of Agricultural, Food and Environment Science (Unit Research of Biochemistry and Molecular Biology), University of Perugia, via Del Giochetto, 06125 Perugia, Italy.
authors: Michela
authors: M
authors: Mazzoni
authors: Department of Agricultural, Food and Environment Science (Unit Research of Biochemistry and Molecular Biology), University of Perugia, via Del Giochetto, 06125 Perugia, Italy.
authors: Letizia
authors: L
authors: Granieri
authors: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto, 8, 06123 Perugia, Italy.
authors: Laura
authors: L
authors: Goracci
authors: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto, 8, 06123 Perugia, Italy.
authors: Angela
authors: A
authors: Scrascia
authors: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto, 8, 06123 Perugia, Italy. Electronic address: susan@chemiome.chm.unipg.it.
authors: Susan
authors: S
authors: Lepri
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002614:Chelating Agents; D004164:Diphosphonates; D007211:Indoles; C030374:indole; D002118:Calcium
keywords: Chelating ability assessment; Cytosolic calcium; Ene reaction; Indole based bisphosphonate