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AICARFT is a folate dependent catalytic site within the ATIC gene, part of the purine biosynthetic pathway, a pathway frequently upregulated in cancers. LSN3213128 is a potent (16 nM) anti-folate inhibitor of AICARFT and selective relative to TS, SHMT1, MTHFD1, MTHFD2 and MTHFD2L. Increases in ZMP, accompanied by activation of AMPK and cell growth inhibition, were observed with treatment of LY3213128. These effects on ZMP and proliferation were dependent on folate levels. In human breast MDA-MB-231met2 and lung NCI-H460 cell lines, growth inhibition was rescued by hypoxanthine, but not in the A9 murine cell line which is deficient in purine salvage. In athymic nude mice, LSN3213128 robustly elevates ZMP in MDA-MB-231met2, NCI-H460 and A9 tumors in a time and dose dependent manner. Significant tumor growth inhibition in human breast MDA-MB231met2 and lung NCI-H460 xenografts and in the syngeneic A9 tumor model were observed with oral administration of LSN3213128. Strikingly, AMPK appeared activated within the tumors and did not change even at high levels of intratumoral ZMP after weeks of dosing. These results support the evaluation of LSN3213128 as an antineoplastic agent.

Structure-based design approach was successfully used to guide the evolution of imidazopyridine scaffold yielding new structural class of highly selective inhibitors of cyclin dependent kinases that were able to form a new interaction with an identified residue of the protein, Lys89. Compounds from this series have shown no detectable effect when tested against a representative set of other serine/threonine kinases such as GSK3beta, CAMKII, PKA, PKC-alpha,beta,epsilon,gamma. Compound 2i inhibits proliferation in HCT 116 cells in tissue culture. Synthesis, co-crystal structure of CDK2 in complex with compound 2i, and preliminary SAR study are disclosed.

The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.

The synthesis and kinase inhibitory activity of a series of novel 1,7-annulated indolocarbazoles 6 and 16 is described. These compounds exhibited potent inhibitory activity against cyclin-dependent kinase 4 and good antiproliferative activity in a human colon carcinoma cell line.

The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an aminoimidazo[1,2-a]pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer and other diseases that involve protein kinase signaling pathways.

A series of indolo[2,3-a]pyrrolo[3,4-c]carbazoles and their bis-indolylmaleimides precursors have been prepared in order to compare their activity as D1-CDK4 inhibitors. Both enzymatic and antiproliferative assays have shown that the structurally more constrained indolo[2,3-a]pyrrolo[3,4-c]carbazoles are consistently more active (8-42-fold) in head-to-head comparison with their bis-indolylmaleimides counterparts. Cell-cycle analysis using flow cytometry have also shown that the indolocarbazoles are selective G1 blockers while the bis-indolylmaleimides arrest cells in the G2/M phase.

The synthesis of new analogues of Arcyriaflavin A in which one indole ring is replaced by an aryl or heteroaryl ring is described. These new series of aryl[a]pyrrolo[3,4-c]carbazoles were evaluated as inhibitors of Cyclin D1-CDK4. A potent and selective D1-CDK4 inhibitor, 7a (D1-CDK4 IC(50)=45 nM), has been identified. The potency, selectivity profile against other kinases, and structure-activity relationship (SAR) trends of this class of compounds are discussed.

A novel series of pyrrolo[3,4-c] carbazoles fused with a quinolinyl/isoquinolinyl moiety were synthesized and their D1/CDK4 inhibitory and antiproliferative activity were evaluated. Compound 8H, 14H-isoquinolinyl[6,5-a]-pyrrolo[3,4-c]carbazole-7,9-dione (1d) was found to be a highly potent D1/CDK4 inhibitor with an IC50 of 69 nM. Compound 1d also inhibited tumor cell growth, arrested tumor cells in G1 phase and inhibited pRb phosphorylation.

The synthesis of a novel series of 1,7-annulated indolocarbazoles 2 and 16 is described. These compounds were found to be potent cyclin dependent kinase inhibitors with good antiproliferative activity against two human carcinoma cell lines. These inhibitors also arrested tumor cells at the G1 phase and inhibited pRb phosphorylation.

The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.

Novel substituted indolocarbazoles were synthesized, and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles 4 were found to be potent and selective D1/CDK4 inhibitors. 4d and 4h exhibited potent and ATP-competitive D1/CDK4 activities with IC50 values of 76 and 42 nM, respectively. Both compounds had high selectivity against the other kinases. These D1/CDK4 inhibitors inhibited tumor cell growth, arrested tumor cells at the G1 phase, and inhibited pRb phosphorylation.

This book is a digital electronics text focused on 'how to' design, build, operate and adapt data acquisition systems. The book is intended to serve people whose goals include teaching or learning one or more of the following: digital electronics, circuit design for computer expansion slots, software which interacts with outside hardware, the process of computer based data acquisition, and the design, adaptation, construction and testing of measurement systems. The fundamental idea of the book is that parallel I/O ports (available for all popular computers) offer a superior balance of simplicity, low cost, speed, flexibility and adaptability.

A critical bibliography of 25 books is presented. It is to aid potential teachers of physics‐and‐society courses in acquiring competence in this subject area.

Mossbauer sources and absorbers, prepared by doping Fe57 and radioactive Co57 into samples of Co1−xV2−xO4 (0 ⩽ x ⩽ 1), were studied in the temperature range of 80–500 K. The source and absorber spectra are very similar. The absence of any Fe2+ at the A site can be understood by partial covalent bond formation with an anion. However, the predominance of Fe3+ at the B site (with some Fe2+ for x = 1) cannot be explained by simple crystal-field or molecular-orbital theories. The x dependence of the isomer shift and of the Fe3+B-site quadrupole interaction can be related to changes in the lattice constant and the oxygen parameter. The temperature dependence of the Fe2+B-site quadrupole interaction can be fitted in the motional-averaging model. In the range of 0 ⩽ x ⩽ 0.5 the temperature dependence of the isomer shift shows effects of chemical bonding beyond the second-order Doppler shift.

The M\"ossbauer spectra produced by ${10}^{\ensuremath{-}4}$-at.% ${\mathrm{Co}}^{57}$ and 0.5-at.% ${\mathrm{Fe}}^{57}$ doped in the normal spinels ${\mathrm{Co}}_{3}$${\mathrm{O}}_{4}$, Co${\mathrm{Rh}}_{2}$${\mathrm{O}}_{4}$, Co${\mathrm{Cr}}_{2}$${\mathrm{O}}_{4}$, Co${\mathrm{Mn}}_{2}$${\mathrm{O}}_{4}$, and Zn${\mathrm{Co}}_{2}$${\mathrm{O}}_{4}$ have been obtained. Based on properties of the spinel structure and on correlations with M\"ossbauer data from the natural-iron spinels, these spectra are interpreted in terms of the daughter and impurity iron being located on the tetrahedral and octahedral lattice sites. The charge state of the daughter iron is not always the same as that of the parent cobalt; instead, it is generally that of natural iron in the parallel spinel compounds ${\mathrm{Fe}}_{3}$${\mathrm{O}}_{4}$, Co${\mathrm{Fe}}_{2}$${\mathrm{O}}_{4}$, Fe${\mathrm{Co}}_{2}$${\mathrm{O}}_{4}$, Fe${\mathrm{Cr}}_{2}$${\mathrm{O}}_{4}$, Fe${\mathrm{Mn}}_{2}$${\mathrm{O}}_{4}$, and Zn${\mathrm{Fe}}_{2}$${\mathrm{O}}_{4}$. From this and other evidence, we propose that the daughter-iron's valence is determined primarily by the chemical bonding properties of iron (as distinct from cobalt) in the environment where it is created. Of the several models of spinel crystal chemistry, that of Goodenough and Loeb roughly accounts for our conclusions.

The goals, teaching methods, and requirements of a six‐year‐old physics‐and‐society course are presented and related to the course’s content and survey approach. The problems, frustrations, and rewards experienced in developing and teaching the course are shared.

Mossbauer source and absorber spectra of FeCo 2 O 4 and Fe 0.5 Co 2.5 O 4 have been obtained between 82 and 523 K. Interpretation of the spectra allow the cation distributions of the compounds to be determined. FeCo 2 O 4 is Co 2+ 0.55 Fe 3+ 0.45 [Co 2+ 0.45 Fe 3+ 0.55 Co 3+ 1.0 ]O 4 and Fe 0.5 Co 2.5 O 4 is Co 1 2+ [Fe 3+ 0.5 Co 3+ 1.5 ]O 4 . Spinel tetrahedral site quadruple splitting is observed in both compounds.

Tetrakis-(4-N-methyl)pyridylporphineiron(III) (FeTMpyP) was synthesized and its aqueous solution properties studied. The visible spectrum of FeTMpyP was found to be dependent on pH and ionic strength. The following equilibria were sufficient to account for the titration data: H 2 O + FeP ( H 2 O ) 5+ ⥂ FeP ( OH )( H 2 O ) 4+ + H + ;p K a1 =4.7±0.2 FeP ( OH )( H 2 O ) 4+ ⥂ FeP (OH) 2 3+ + H + ; p K a2 =6.5±0.3 2 FeP ( OH ) 2 3+ ⥂O−( FePOH ) 2 6+ + H 2 O ; K D ≃9×10 5 M −1 . Magnetic susceptibility measurements and Mossbauer spectroscopy were used to characterize the FeTMpyP species at low and high pH. In the range pH 1–3, monomeric, high-spin, pentacoordinated iron(III) is the primary species. A μ-oxo dimer involving low-spin hexacoordinated iron(III) exists at pH 10–12. The rate of dissociation of the dimer at μ = 0.05 M and t = 25°C was found a two-term rate law: − d [ dimer ] d t =(k 1 +k′ 1 [ H + ])[ dimer ] where k1 = 0.42 sec−1 and K1 = 31 M−1 sec−1. These results are compared with those obtained for the dissociation of dimer of tetraphenylporphinesulfonatoferrate(III), FeTPPS.

The Mossbauer determined cation distributions of FeV2O4, FeCr2O4, FeMn2O4, Fe3O4, FeCo2O4, CoV2O4, CoCr2O4, CoMn2O4, CoFe2O4 and Co3O4 are compared with the quantitative d-orbital stablization energies of McClure and of Dunitz and Orgel. They are also compared with the qualitative ligand field stabilization energies of Cotton. These theories do not account for observation in the cases of FeMn2O4, FeCo2O4 and CoFe2O4.

A review is presented of contributions which Mossbauer spectroscopy can make to studies of radiation-damage effects. Special emphasis is placed on the unique aspects of this technique, including the following examples: in all Coulomb excitation, as well as in some radioactive decay processes, every Mossbauer gamma ray has its origin in a radiation-damage event, leading to high sensitivity; all chemical charge states of a Mossbauer ion can be simultaneously observed and identified through the isomer shift; the Mossbauer effect is particularly sensitive to the local details of the damage effects; and radiation-damage processes with recovery times as short as the nuclear lifetimes can be studied. Some of the more significant contributions of the Mossbauer effect to a variety of radiation-damage questions are illustrated by reviewing experiments from the existing literature.

Mossbauer source and absorber studies have been carried out on the spinel system CoFexRh2−xO4 for x = 0.005, 0.3, 0.5, 1.0, 1.2 and 1.5. For 0.005 ⩽ x ⩽ 1.2, the cation distribution is normal with Co2+ on Asites. At x = 1.5, the distribution is nearly inverse. In the cases x = 0.005 and 0.3, iron on the B sites does not produce a quadrupole doublet indicating that the B sites are cubic which is contrary to the usual case in spinels.