Novel acyclic nucleotide phosphonates against RNA viruses

Includes bibliographical references.Acyclic nucleotide phosphonates (ANPs) have been used for years as successful anti-viral agents against diseases such as HIV/AIDS and hepatitis while the drug ribavirin is one of the only drugs available for the treatment of RNA-viral infections which mainly affect the developing world. The large and unmet need for anti-RNA viral treatments has prompted this study into the design and synthesis of a range of ANPs, which includes a series of ribavirin-based ANP derivatives. The series of compounds was synthesised from a diisopropyl protected phosphonomethoxyethyl (PME) synthon and included an arylethynyltriazole derivative which was produced via a Sonogashira palladium catalysed cross-coupling reaction. A selection of these compounds was then deprotected to their corresponding phosphonic acids via a bromotrimethylsilane mediated phosphonate ester hydrolysis. In one example, a bis(pivaloyloxymethyl) prodrug variant was produced in order to probe a general synthesis for prodrug protected ANP derivatives. All new compounds were characterised by NMR, IR, and Mass spectroscopic techniques

Studies in the Sugar Alcohol, Steroid and Heterocyclic Series

Abstract Not Provided

SYNTHESIS OF a,ß-UNSATURATED-1,3-DIKETONES AND RELATED MANNICH BASES FOR EVALUATION AGAINST VARIOUS NEOPLASMS

In the chemical warfare against cancer, different classes of drugs are employed. However, since a majority of these drugs have been developed with a common target in mind, namely DNA, they have the potential of being carcinogenic and mutagenic. In addition they are associated with host toxicity and drug resistance. Hence, there is a need for new anticancer drugs especially those which have greater toxicity for neoplasms than normal tissues. Mannich bases have been found to display a wide range of biological activities. Earlier workers from these laboratories have established the potentiality of some of these compounds as antineoplastic agents. Based on kinetic and physicochemical considerations resulting from these studies, the synthesis of a number of Mannich bases derived from some substituted 3-arylmethylene-, 3- heteroarylmethylene- and 3-aralkenylmethylene diketones has been accomplished and the compounds were evaluated against P388 lymphocytic leukemia in mice. The Mannich bases derived from the 1,3-diketones mentioned above could be divided into two groups, namely (1) monoaminomethylated Mannich bases and (2) bisaminomethylated Mannich bases. Of these compounds, while (2), with the exception of the cinnamylidene derivative, were uniformly inactive against P388 lymphocytic leukemia in an in vivo screen, some representative compounds from (2), viz., bis Mannich bases of p-hydroxy and p-methoxy benzylidene diketones, were active in the in vitro screen against a number of tumour systems. These two compounds were designated Selected Agent Compounds by the National Cancer Institute, USA, and were screened or are in the process of being screened against a number of other tumours in vivo. Compounds belonging to (1) showed variable and sometimes, appreciable activity. Two compounds belonging to series (1), viz., the 3,4-dichloro and the terephthalidene analogs were designated Selected Agent Compounds by the National Cancer Instiute, USA, and were screened or are being screened against a number of other tumours in mice

Post-Amadori Reactions of Serum Proteins

The formation of glycofluorophores and the fragmentation of proteins is only seen if glucose (or another reducing sugar) is included in the incubation. Although similar changes have been reported in the absence of sugars, it has been shown here that these changes are glucose dependent. Contrary to previous work, I have shown that the presence of bound lipid on HSA does not alter the formation of Amadori product. Fragmentation of HSA is also unaffected by the presence ofbound lipid, but the formation of fluorescence by native HSA is 2.5 times greater than that of delipidated HSA. This shows that (i) tire enhanced fluorophore formation seen in native HSA is independent of the amount of Amadori product, (ii) that at least two con^onents of fluorescence on native HSA exist and (iii) that the mechanisms of fragmentation and lipid-dependent fluorescence formation are not the same. Both fragmentation and fluorescence formation were inhibited by the transition-metal chelator DTPA, low ing that both these reactions are transition-metal catalysed. The formation of glycofluorophores appears to be partially dependent on the high affnity binding of transition metals to the protein, but the glucose-induced fragmentation of both albumin and human transferrin occurs only when the transition metal species present is copper. No fragmentation of the iron binding protein transferrin is seen when iron is included in the incubations in the place of copper. Both these reactions were also inhibited by the use of HEPES buffer in the place of phosphate buffer. HEPES buffer, unlike phosphate buffer, has free radical scavenging properties so therefore it would appear that in addition to being transition-metal catalysed, these reactions are free radical mediated processes. The carbonyl scavenger, aminoguanidine, inhibited the production of glycofluorophores implicating a carbonyl intermediate in this reaction. Pre-incubation of glucose with copper caused an increase in the amount of fluorescence initially observed indicating that autoxidation of glucose plays a role in fluorophore formation, although it is not possible to say whether this is a major reaction pathway or not

Oxidative Reactions of Some Tetracyclic Diterpenoids

Abstract Not Provided