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Syntheses and biological activities of 2-phosphonylmethoxy-ethyl (PME) purine analogs are described.

Stereoselective syntheses of the 1-β-methylcarbapenem intermediates 9B (R=SPh or OCH3) have been accomplished by an aldol-type stereocontrolled reaction and stereoselective catalytic hydrogenation of an olefinic ester.

The synthesis of new carbapenems having various (substituted) quaternary heterocyclic alkylthio groups at the C-2 position is described. The in vitro antibacterial activity and the dehydropeptidase-I susceptibility were examined. Some of these compounds (e.g., 11, 16, 26 and 27) showed an excellent wide spectrum of in vitro antibacterial activity including activity against Pseudomonas aeruginosa and greater stability than imipenem toward the dehydropeptidase-I.

Novel carbon nucleophilic displacement reactions on Kamiya's azetidinone disulfide 2 and the synthesis of the C-2 modified penams 25 , 26 and 27 from the intermediates 8 , 9 , and 11 are described.

2,6-Dimethoxybenzyl esters are readily oxidized by 2,3-dichloro-5,6-dicyano benzoquinone (DDQ) to generate the corresponding carboxylic acids. Phenyl esters substituted with hydroxy, methoxy and dimethylamino groups are also efficiently oxidized by ceric ammonium nitrate (CAN) under pH control conditions.

Stereoselective syntheses of the 1-β-methylcarbapenem intermediates 9B (R=SPh or OCH3) have been accomplished by an aldol-type stereocontrolled reaction and stereoselective catalytic hydrogenation of an olefinic ester.

The first reported synthesis of 2-oxocephalosporin derivatives has been achieved via ozonolysis of the corresponding 2-methylenecephalosporins. The new cephalosporin derivatives showed some antibacterial activity against Gram-positive bacteria, but the 2-oxo analogue of cephalothin was much less active than cephalothin itself.

The synthesis and in vitro activities of a series of 2-[(methoxycarbonyl)methylene]-3-cephem-4-carboxylic acids with methyl or acetoxymethyl at the 3-position are described. The key step in the synthesis includes the stereospecific formation of the 2-[(Z)-(methoxycarbonyl)methylene] group by Pummerer rearrangement of the sulfoxides 3a and 3b. It was also possible to isomerize photochemically the C-2 olefin of 4a to its E isomer, 9. The new derivatives exhibited significant in vitro Gram-positive antibacterial activity.

The first reported synthesis of 2-oxocephalosporin derivatives has been achieved via ozonolysis of the corresponding 2-methylenecephalosporins. The new cephalosporin derivatives showed some antibacterial activity against Gram-positive bacteria, but the 2-oxo analogue of cephalothin was much less active than cephalothin itself.

The synthesis and in vitro activities of a series of 2-[(methoxycarbonyl)methylene]-3-cephem-4-carboxylic acids with methyl or acetoxymethyl at the 3-position are described. The key step in the synthesis includes the stereospecific formation of the 2-[(Z)-(methoxycarbonyl)methylene] group by Pummerer rearrangement of the sulfoxides 3a and 3b. It was also possible to isomerize photochemically the C-2 olefin of 4a to its E isomer, 9. The new derivatives exhibited significant in vitro Gram-positive antibacterial activity.

New 1 beta-methylcarbapenems having various (substituted) quaternary heterocyclic alkythio groups at the C-2 position were synthesized and tested for antibacterial activity and renal dipeptidase susceptibility. Compounds having the 1 beta-methyl substituent were found to possess an increased stability to the enzyme. In addition, combination of the 1 beta-methyl substituent and the C-2 quaternary heterocyclic alkylthio side chain generated compounds with excellent antipseudomonal activity and improved stability toward hydrolysis by renal dipeptidase.

To overcome the low oral bioavailability of the highly potent and selective antiretroviral agent ( R )-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a new lipophilic ester derivative, i.e., the bis(isopropyloxycarbonyloxymethyl)-ester [bis(POC)-PMPA], was prepared. The usefulness of bis(POC)-PMPA as an oral prodrug for PMPA was investigated in the intestinal mucosa Caco-2 cell monolayer model. The total transport of bis(POC)-PMPA was 2.7%, whereas it was less than 0.1% for PMPA. Bis(POC)-PMPA was considerably metabolized inside the epithelial cells, since the majority of the compound was recovered after transport in the form of the monoester metabolite [mono(POC)-PMPA]. In contrast, bis(POC)-PMPA was relatively resistant to degradation at the luminal side of the Caco-2 cells. Pharmacokinetic studies with mice showed that the oral bioavailability of bis(POC)-PMPA (calculated from the curves of the concentration of free PMPA in plasma) was 20%. Neither bis(POC)-PMPA nor mono(POC)-PMPA could be recovered in plasma, suggesting the efficient release of the active drug PMPA after oral administration of bis(POC)-PMPA. Severe combined immunodeficient (SCID) mice infected with Moloney murine sarcoma virus (MSV) and treated orally with bis(POC)-PMPA for 5 or 10 days (dosages, 50, 100, or 200 mg of PMPA equivalent per kg of body weight per day) showed a significant delay in MSV-induced tumor appearance and tumor-associated death. The antiviral efficacy of oral bis(POC)-PMPA was related to the dosage and treatment period and was not significantly different from that of subcutaneous PMPA given at an equivalent dose. The favorable pharmacokinetic profile, marked antiviral efficacy, and low toxicity make bis(POC)-PMPA an attractive oral prodrug of PMPA that should be further pursued in clinical studies with patients infected with human immunodeficiency virus or hepatitis B virus.