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We have examined the radiolysis of an O2-free aqueous solution of glycine at absorbed doses of 60Co gamma-radiation of up to 20 Mrad. At least 20 compounds are formed during radiolysis, among them several amino acids, an oligoamine, and the nitrogen-free polymers (Mw less than or equal to 28,000 daltons). When dicyandiamide is present in the solution of glycine, various nitrogen-containing products, including some polymers (Mw less than or equal to 12,000 daltons), are synthesized along with radiolytic products of glycine; polyglycines are not formed. We have determined the radiation-chemical yields of radiolytic-product formation and of decomposition of glycine, and have considered possible free-radical reactions leading to the radiation-induced changes observed.
Dilute (0.1 M) solutions of HCN condense to oligomers at pH 8-9. Hydrolysis of these oligomers at pH 8.5 or with 6 N HCl yields 4,5-dihydroxypyrimidine, as the most abundant pyrimidine product along with orotic acid and 5-hydroxyuracil. These results, together with the earlier data, demonstrate that the three major nitrogen-containing classes of biomolecules could have originated from HCN on the primitive earth. The observation of the formation of orotic acid and 4-aminoimidazole-5-carboxamide by the hydrolysis of the HCN oligomers suggests that once the initially formed pyrimidines and purines were consumed, those life forms persisted which evolved enzymes for conversion of these intermediates to the pyrimidines and purines present in contemporary RNA.
In the past decade, significant progress has been made in understanding structure-function relationships of the new quinolones, which have a N-1-substituted, 1,4-dihydro-4-oxo-pyridine-3-carboxylic acid moiety as the basic nucleus. Modification of the groups affixed to positions C-6, C-7, and C-8 has made a major change in the antimicrobial activity, pharmacokinetic, and metabolic properties of the quinolones as have changes in the moieties affixed to the N-1 nitrogen. The new quinolones have a carboxyl group at position 3 and a keto group at C-4. The presence of a fluorine atom at C-6 enhances the deoxyribonucleic acid (DNA) gyrase inhibitory activity as well as the ability of the compounds to inhibit staphylococci. Position C-7 has been one of the most modified sites. Addition of a piperazinyl group markedly increased gram-positive activity, primarily antistaphylococcal activity; lowered the minimal inhibitory concentrations against Enterobacteriaceae, Haemophilus spp., and Neisseria spp.; and added activity against Pseudomonas aeruginosa compared with nalidixic acid. Methyl derivatives of the piperazine group or of the pyrroles have longer half-lives than do unsubstituted moieties. At the N-1 position, a cyclopropyl group appears to be most potent with respect to minimal inhibitory concentrations against Enterobacteriaceae and Pseudomonas. Ofloxacin is unique in that it has an oxygen substituted at C-8 with the substituent part of the ring system formed by fusion to the N-1 position. This has produced excellent in vitro activity against gram-positive species comparable with that of ciprofloxacin, excellent activity against the Enterobacteriaceae, and antipseudomonal activity superior to agents with an ethyl substitution at position N-1. The oxazine ring of ofloxacin provides excellent oral absorption with virtually 95 percent bioavailability; this modification also has prevented metabolism and has provided a long half-life of seven to eight hours.
Two discovery approaches directed to addressing the problem of increasing bacterial resistance are described. The first is a program to build activity against methicillin-resistant Staphylococcus aureus (MRSA) into the cephalosporin class of antibacterials, by enhancing affinity for PBP2a, the penicillin-binding protein responsible for this resistance. Through stepwise improvement in potency, human serum binding, solubility, and betalactamase stability, a stable of new compounds with excellent potential as anti-MRSA agents was realized. From this set was chosen MC-02, 479 (RWJ-54428), which is now undergoing extensive preclinical evaluation. The second approach explores the uridyl peptide family of antibiotics, inhibitors of bacterial translocase (mraY), whose members include the pacidamycins, mureidomycins, and napsamycins. Access to a diverse set of analogs by total synthesis was catalyzed by the discovery that hydrogenation of the 4'-exoenamidofuranosyl moiety causes no loss in biological activity. Indepth exploration of SAR required (1) establishment of the absolute stereochemistry of the central diaminobutyric acid (DABA) moiety and (2) determination of the stereochemistry of the 4'-substituent on the deoxyfuranose unit. The former was accomplished by comparison of DABA derived from degradation of a natural product pacidamycin with a sample synthesized from L-threonine. The biological activity of one member of a synthesized library of possible stereoisomers of the natural product established the absolute stereochemistry of the remaining centers. A variety of analogs of the natural product were prepared utilizing the synthetic methods developed, and their biological activities provide important insights into the specificity and spectrum of the antibiotic class.
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The photochemical reaction of HCN at 184.9 nm is studied in the gas phase. (CN)2, H2, CH4, NH3, N2H4, C2H6, and CH3NH2 are identified as gas phase products, and a reaction mechanism is proposed. HCN polymers are also obtained as solid reaction products, and their structure is investigated by Infrared Spectorscopy, UV-Visible Spectroscopy, Mass Spectrometry, and Amino Acid Analysis. The process and nature of the formation of the polymers are discussed.
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The effect of the exchangeable cation on the condensation of glycine and alanine was investigated using a series of homoinic bentonites. A cycling procedure of drying, warming and wetting was employed. Peptide bond formation was observed, and the effectiveness of metal ions to catalyze the condensation was Cu2+ greater than Ni2+ approximately Zn2+ greater than Na+. Glycine showed 6% of the monomer incorporated into oligomers with the largest detected being the pentamer. Alanine showed less peptide bond formation (a maximum of 2%) and only the dimer was observed.