New symmetrically esterified m-bromobenzyl non-aminobisphosphonates inhibited breast cancer growth and metastases.
BACKGROUND
Although there was growing evidence in the potential use of Bisphosphonates (BPs) in cancer therapy, their strong osseous affinities that contrast their poor soft tissue uptake limited their use. Here, we developed a new strategy to overcome BPs hydrophilicity by masking the phosphonic acid through organic protecting groups and introducing hydrophobic functions in the side chain.


RESULTS
We synthesized non-nitrogen BPs (non N-BPs) containing bromobenzyl group (BP7033Br) in their side chain that were symmetrically esterified with hydrophobic 4-methoxphenyl (BP7033BrALK) and assessed their effects on breast cancer estrogen-responsive cells (T47D, MCF-7) as well as on non responsive ones (SKBR3, MDA-MB-231 and its highly metastatic derived D3H2LN subclone). BP7033Br ALK was more efficient in inhibiting tumor cell proliferation, migration and survival when compared to BP7033Br. Although both compounds inhibited tumor growth without side effects, only BP7033Br ALK abrogated tumor angiogenesis and D3H2LN cells-induced metastases formation.


CONCLUSIONS
Taken together these data suggest the potential therapeutic use of this new class of esterified Bisphosphonates (BPs) in the treatment of tumor progression and metastasis without toxic adverse effects.
Abdelkarim
Mohamed
M
Université Paris 13, CNRS FRE CSPBAT, Laboratoire de Chimie Structurale Biomoléculaire, Laboratoire de pharmacologie, Université Paris 13, UFR SMBH, Bobigny, France.
Guenin
Erwann
E
Sainte-Catherine
Odile
O
Vintonenko
Nadejda
N
Peyri
Nicole
N
Perret
Gerard Yves
GY
Crepin
Michel
M
Khatib
Abdel-Majid
AM
Lecouvey
Marc
M
Di Benedetto
Mélanie
M
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D004951:Esterification; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004164:Diphosphonates