Mark J. Suto

Ion-exchange resins for solution phase parallel synthesis of chemical libraries

Abstract Described are various techniques that employ ion-exchange resins for the solution-phase synthesis of chemical libraries. We have found these resins to be useful as reagents and/or scavengers in a variety of reactions. Nine basic ion-exchange resins were evaluated for the catalysis and purification of an amide synthesized from an acid chloride. A number of the resins examined provided products in >95% purity. Acidic ion-exchange resins were also useful as scavengers in the synthesis of ureas. A demonstration of the utility of these resins for the preparation of amide, ester and urea libraries is also described.

Traceless linker: Oxidative activation and displacement of a sulfur-based linker

Abstract The construction of small heterocycles using solid-phase chemistry is usually done through the use of a polar group to attach the compounds to the resin. These polar functionalities invariably become part of the structure and eventually limit the structure-activity relationships derived from these compounds. We have identified a method for overcoming some of these limitations. A sulfur-based linker has been identified that can serve not only as a point of attachment for a small heterocycle, but also as a means to introduce further diversity into the molecule. The linker remains inert until “activated” by oxidation. A limiting amount of a nucleophile can then be used to cleave the molecule from the resin and introduce additional diversity into the molecule.

Effects of PD 128763, a New Potent Inhibitor of Poly(ADP-Ribose) Polymerase, on X-Ray-Induced Cellular Recovery Processes in Chinese Hamster V79 Cells'

The modifying effects of PD 128763 (3,4-dihydro-5-methyl-1(2H)-isoquinolinone), a potent inhibitor of poly(adenosine-diphosphate (ADP)-ribose) polymerase, on radiation-induced cell killing were examined in Chinese hamster V79 cells. This compound has an IC50 value against the purified enzyme approximately 50X lower than 3-aminobenzamide (3-AB), a widely used specific inhibitor of the enzyme. Exposure of exponentially growing cells to a noncytotoxic concentration (0.5 mM) of PD 128763 for 2 h immediately following X irradiation increased their radiation sensitivity, modifying both the shoulder and the slope of the survival curve. When recovery from sublethal damage and potentially lethal damage was examined in exponential and plateau-phase cells, respectively, postirradiation incubation with 0.5 mM PD 128763 was found not only to inhibit both these processes fully, but also to enhance further the level of radiation-induced cell killing. This is in contrast to the slight effect seen with the less potent inhibitor, 3-AB. The results presented suggest that the mechanism of radiosensitization by PD 128763 is related to the potent inhibition of poly(ADP-ribose) polymerase by this compound.

2-nitroimidazole derivatives useful as radiosensitizers for hypoxic tumor cells

Certain α-[(2-nitro-1H-imidazol-1-yl)methyl]-aziridinylethanols and the corresponding aziridine-ring opened analogs are useful as radiation sensitizers for X-irradiation therapy of tumors.

Stereoselective Michael additions of nitromethane yielding 3R(1S N-substituted aminoethyl)pyrrolidines

Abstract The 1,4-addition of nitromethane to vinylogous esters of N-protected amino acids proceeded with good to excellent yields and with good diastereoselectivity.

Use of pentafluorophenyl esters for one-pot protection/activation of amino and thiol carboxylic acids

Abstract As part of our efforts in the area of combinatorial chemistry, we have been exploring new methods for the construction of combinatorial libraries in a bidirectional fashion. Herein, we describe a new one-pot procedure for the simultaneous protection/activation of amino and thiol carboxylic acids using pentafluorophenyl trifluoroacetate (TFAPfp) and related pentafluorophenyl reagents (FmocPfp and AcPfp).

Synthesis of Boxazomycin B and related analogs

Abstract The total synthesis of the novel antibacterial agent Boxazomycin B is reported. The synthesis proceeds through a highly functionalized benzene ring in which the key functionalities are introduced early in the synthesis and serve as protecting groups for additional transformations.

3-Ethenyl, 3-ethynyl, 3-aryl, and 3-cyclopropyl-2,4,5-trifluorobenzoic acids: Useful intermediate in the synthesis of quinolone antibacterials

The synthesis of 3-ethenyl, 3-ethynyl, 3-aryl, and 3-cyclopropyl-2, 4, 5-trifluorobenzoic acids from 1-bromo-2, 4, 5-trifluorobenzene and 2, 4, 5-trifluoro-3-hydroxybenzoic acid is described. These compounds are useful intermediates for the synthesis of quinolone antibacterials.

Pharmacologic/pharmacokinetic evaluation of emesis induced by analogs of RSU 1069 and its control by antiemetic agents.

RB 6145, the ring-opened analog of RSU 1069, and PD 130908, the desoxy ring-opened analog of RSU 1069, were compared to RSU 1069 for their emetic potential in dogs. When RB 6145 and PD 130908 were administered intravenously at doses ranging from 20% to 50% of the mouse equivalent maximum tolerated dose (MTD), both analogs were less emetic than RSU 1069 on a molar basis. Furthermore, the 5HT3 antagonist ondansetron prevented emesis at doses as high as 75% of the MTD. The reactivity, and hence the emetic liability of these compounds, is thought to be mediated by formation of the corresponding aziridine intermediate. In mouse plasma, both analogs rapidly converted to two products, the reactive aziridine and a stable oxiazolidinone species formed upon reaction with bicarbonate in the blood. A positive correlation exists between the amounts of aziridine formed by these analogs and their emetic potential.

An efficient method for the synthesis of (R)-3-(1-amino-1-methylethyl)pyrrolidines for the antiinfective agent, PD 138312

Abstract Methylcerium dichloride has been found to undergo bis addition to nitriles to produce tertiary carbinamines with retention of optical purity at the α position. This result is used in the development of a short, economical synthesis of the 1,8-naphthyridine antiinfective agent, PD 138312.