Potent double prodrug forms of synthetic phosphoantigens.
Bioorg Med Chem
; 28(19): 115666, 2020 10 01.
Article
en En
| MEDLINE
| ID: mdl-32912439
ABSTRACT
Phosphoantigens are ligands of BTN3A1 that stimulate anti-cancer functions of γδ T cells, yet the potency of natural phosphoantigens is limited by low cell permeability and low metabolic stability. Derivatives of BTN3A1 ligand prodrugs were synthesized that contain an acetate-protected allylic alcohol and act as doubly protected prodrugs. A novel set of phosphonates, phosphoramidates, and phosphonamidates has been prepared through a new route that simplifies synthesis and postpones the point of divergence into different prodrug forms. One of the new prodrugs, compound 11, potently stimulates γδ T cell proliferation (72 h EC50 = 0.12 nM) and interferon γ response to loaded leukemia cells (4 h EC50 = 19 nM). This phosphonamidate form was > 900x more potent than the corresponding phosphoramidate, and the phosphonamidate form was also significantly more stable in plasma following acetate hydrolysis. Therefore, prodrug modification of phosphonate butyrophilin ligands at the allylic alcohol can both facilitate chemical synthesis and improve potency of γδ T cell stimulation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Compuestos Organofosforados
/
Profármacos
/
Antígenos CD
/
Butirofilinas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos