ABSTRACT
Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Immunotherapy , Lung Neoplasms/therapy , Pyrophosphatases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Thioguanine/pharmacology , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Female , Humans , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Molecular Structure , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/therapy , Phosphoric Diester Hydrolases/metabolism , Pyrophosphatases/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Thioguanine/chemical synthesis , Thioguanine/chemistryABSTRACT
The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine are described. The crystal structures and pKa values of these and related O6-methylguanine analogues are reported. All compounds display higher pKa values than O6-methylguanine with the sulfur-containing analogues being the more basic and exhibiting higher stability in aqueous solution. In a standard substrate assay with the human repair protein O6-methylguanine-DNA methyltransferase (MGMT) only the oxygen-containing analogue displayed activity.
Subject(s)
Guanine/analogs & derivatives , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Thioguanine/analogs & derivatives , Crystallography, X-Ray , Guanine/chemical synthesis , Guanine/chemistry , Guanine/metabolism , Humans , Hydrogen-Ion Concentration , Molecular Structure , O(6)-Methylguanine-DNA Methyltransferase/metabolism , Substrate Specificity , Thioguanine/chemical synthesis , Thioguanine/chemistry , Thioguanine/metabolismABSTRACT
Organomercury(II) complexes involving 6-thioguanine, of the type p-XC6H4HgL (Fig. 1) [LH = 6-thioguanine; X = Me, MeO, NO2], have been synthesized and characterized. Conductance measurements indicate that the complexes are nonelectrolytes. From IR and UV studies, it is concluded that 6-thioguanine acts as a bidentate ligand, coordinating through the 6-thione group and deprotonation of N-7. 1H and 13C NMR support the stoichiometry of the complexes. From thermal studies (TG and DSC) various kinetic and thermodynamic parameters for thermal degradation have been enumerated. In addition, the fragmentation pattern of the complexes have been analyzed on the basis of mass spectra. The p-MeC6H4HgL and p-MeOC6H4HgL complexes display significant activity against L1210 leukemia cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Organomercury Compounds , Thioguanine/analogs & derivatives , Thioguanine/chemical synthesis , Animals , Calorimetry, Differential Scanning , Cell Survival/drug effects , Kinetics , Leukemia L1210 , Ligands , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Structure-Activity Relationship , Thermodynamics , Thioguanine/pharmacologyABSTRACT
Selenoguanine- and selenoguanosine-platinum(II) complexes were synthesized, and their atitumor activities against L1210 in mice and against in vitro tissue culture system were studied. These compounds exhibited antitumor activity of medium strength and showed very low toxicity. The effect of the SeG-Pt (II) complex in mice was retained longer than that of the parent compound SeG because the SeG-Pt (II) complex very slowly released SeG into blood.
