78715-59-0Relevant articles and documents
Synthesis and Immunomodulatory Activity of Fluorine-Containing Bisphosphonates
Mizuta, Satoshi,Tagod, Mohammed S. O.,Iwasaki, Masashi,Nakamura, Yoichi,Senju, Hiroaki,Mukae, Hiroshi,Morita, Craig T.,Tanaka, Yoshimasa
supporting information, p. 462 - 468 (2019/02/01)
Immune checkpoint blockade using anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, many types of cancer do not respond and for those that do, only a minority of patients achieve durable remissions. Therefore, oncoimmunologists are working to develop adoptive cell therapies for non-hematopoietic tumors by harnessing immune effector cells such as αβ T cells and γδ T cells. In contrast to conventional αβ T cells that recognize peptides in the context of MHC class I or II molecules, γδ T cells expressing Vγ2Vδ2 T cell receptors (also termed Vγ9Vδ2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin-3A1-dependent manner. Vγ2Vδ2 T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine-containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2 T-cell-mediated cytotoxicity, and also promoted the expansion of peripheral blood Vγ2Vδ2 T cells. These results demonstrate that a prodrug of a fluorine-containing zoledronate analogue can sensitize tumor cells for killing as well as expand Vγ2Vδ2 T cells for adoptive cell therapy.
Synthesis and polymerase incorporation of β,γ-modified α-L-threofuranosyl thymine triphosphate mimics
Chen, Zhe,Meek, Kirsten N.,Rangel, Alexandra E.,Heemstra, Jennifer M.
, p. 3958 - 3962 (2016/08/01)
Three β,γ-modified α-L-threofuranosyl nucleoside triphosphates were synthesized. The β,γ-modified tTTPs undergo a single incorporation event with HIV RT but undergo multiple incorporations to form full-length product with engineered thermophilic polymeras
Synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold
Erixon, Karl M.,Dabalos, Chester L.,Leeper, Finian J.
experimental part, p. 3561 - 3572 (2009/02/05)
Novel triazole-based pyrophosphate analogues of thiamine pyrophosphate (TPP) have been synthesised and tested for inhibition of pyruvate decarboxylase (PDC) from Zymomonas mobilis. The thiazolium ring of thiamine was replaced by a triazole in an efficient two-step procedure. Pyrophosphorylation then gave extremely potent triazole inhibitors with KI values down to 20 pM, compared to a KD value of 0.35 μM for TPP. This triazole scaffold was used for further investigation and six analogues containing mimics of the pyrophosphate group were synthesised and tested for inhibition of PDC. Several effective analogues were found with KI values down to around 1 nM.
