8 research outputs found
Isolation, structural elucidation and in vitro activity of 2-acetyl-2-decarboxamido-oxytetracycline against environmental relevant bacteria, including tetracycline-resistant bacteria
Synthesis and antitumor effect in vitro and in vivo of substituted 1,3-dihydroindole-2-ones
Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship
Existing pharmacological
inhibitors for nicotinamide phosphoribosyltransferase
(NAMPT) are promising therapeutics for treating cancer. By using medicinal
and computational chemistry methods, the structure–activity
relationship for novel classes of NAMPT inhibitors is described, and
the compounds are optimized. Compounds are designed inspired by the
NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In
comparison with recently published derivatives, the new analogues
exhibit an equally potent antiproliferative activity in vitro and
comparable activity in vivo. The best performing compounds from these
series showed subnanomolar antiproliferative activity toward a series
of cancer cell lines (compound <b>15</b>: IC<sub>50</sub> 0.025
and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively)
and potent antitumor in vivo activity in well-tolerated doses in a
xenograft model. In an A2780 xenograft mouse model with large tumors
(500 mm<sup>3</sup>), compound <b>15</b> reduced the tumor volume
to one-fifth of the starting volume at a dose of 3 mg/kg administered
ip, bid, days 1–9. Thus, compounds found in this study compared
favorably with compounds already in the clinic and warrant further
investigation as promising lead molecules for the inhibition of NAMPT
The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.
APO866 inhibits nicotinamide phosphoribosyltransferase (NMPRTase), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Intracellular NAD is essential for cell survival, and NAD depletion resulting from APO866 treatment elicits tumor cell death. Here, we determine the in vitro and in vivo sensitivities of hematologic cancer cells to APO866 using a panel of cell lines (n = 45) and primary cells (n = 32). Most cancer cells (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL], and T-cell lymphoma), but not normal hematopoietic progenitor cells, were sensitive to low concentrations of APO866 as measured in cytotoxicity and clonogenic assays. Treatment with APO866 decreased intracellular NAD and adenosine triphosphate (ATP) at 24 hours and 48 to72 hours, respectively. The NAD depletion led to cell death. At 96 hours, APO866-mediated cell death occurred in a caspase-independent mode, and was associated with mitochondrial dysfunction and autophagy. Further, in vivo administration of APO866 as a single agent prevented and abrogated tumor growth in animal models of human AML, lymphoblastic lymphoma, and leukemia without significant toxicity to the animals. The results support the potential of APO866 for treating hematologic malignancies