Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9Hyl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a K i value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5′-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC 50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.

We study an online unit-job scheduling problem arising in buffer management. Each job is specified by its release time, deadline, and a nonnegative weight. Due to overloading conditions, some jobs have to be dropped. The goal is to maximize the total weight of scheduled jobs. We present several competitive online algorithms for various versions of unit-job scheduling, as well as some lower bounds on the competitive ratios.We first give a randomized algorithm RMIX with competitive ratio of e/(e − 1) ≈ 1.582. This is the first algorithm for this problem with competitive ratio smaller than 2.Then we consider s-bounded instances, where the span of each job (deadline minus release time) is at most s. We give a 1.25-competitive randomized algorithm for 2-bounded instances, matching the known lower bound. We also give a deterministic algorithm EDF α , whose competitive ratio on s-bounded instances is 2 − 2/s + o(1/s). For 3-bounded instances its ratio is φ ≈ 1.618, matching the known lower bound.In s-uniform instances, the span of each job is exactly s. We show that no randomized algorithm can be better than 1.25-competitive on s-uniform instances, if the span s is unbounded. For s = 2, our proof gives a lower bound of 4 − 2 √ 2 ≈ 1.172. Also, in the 2-uniform case, we prove a lower bound of √ 2 ≈ 1.414 for deterministic memoryless algorithms, matching a known upper bound. Finally, we investigate the multiprocessor case and give a 1/(1 − ( m m+1 ) m )-competitive algorithm for m processors. We also show improved lower bounds for the general and s-uniform cases.

A set of molecules in which a glucose moiety is bound to a hydrogenable synthon has been synthesized and evaluated for hydrogenation reactions and for the corresponding para-hydrogen-induced polarization (PHIP) effects, in order to select suitable candidates for an in vivo magnetic resonance imaging (MRI) method for the assessment of glucose cellular uptake. It has been found that amidic derivatives do not yield any polarization enhancement, probably due to singlet-triplet state mixing along the reaction pathway. In contrast, ester derivatives are hydrogenated in high yield and afford enhanced (1)H and (13)C NMR spectra after para-hydrogenation. The obtained PHIP patterns are discussed and explained on the basis of the calculated spin level populations in the para-hydrogenated products. These molecules may find interesting applications in (13)C MRI as hyperpolarized probes for assessing the activity of glucose transporters in cells.

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