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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2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the α- and γ-carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of α,γ-diesters and α-monoesters enhanced chemical stability and provided excellent oral exposure in mice, but these mixed esters were too stable in vivo, resulting in minimal release of 1. By introducing POC groups on both the phosphonate and α-carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog.

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Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC and a 1.7-fold improvement in brain AUC with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.

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