This Is AuburnElectronic Theses and Dissertations

Exploring sinefungin analogs as potential antiviral agents




Shulyak, Tetyana

Type of Degree



Chemistry and Biochemistry


Sinefungin bears a strong structural resemblance to S-adenosylmethionine and S-adenosylhomocysteine and, therefore is one of the most potent inhibitors of viral mRNA methyl transferase. Besides antiviral activity, sinefungin was found to have a variety of other biological effects including antifungal, amoebicidal and antiparasitical activities. However, clinical use of natural sinefungin is restricted because of its severe toxicity and very serious side effects. To develop new antiviral agents retaining sinefungin-based antiviral activity while eliminating possible instability related to phosphorolysis of furanosyl nucleosides, carbocyclic sinefungin analogs are compounds of great scientific interest. In considering approaches to carbocyclic sinefungin, it was recognized that construction of the cyclopentane ring system with a sinefungin side-chain would be a challenging task. For this purpose compounds I and II became targets to develop a method for the construction of 5'-C chain on the carbocyclic ring. After we discovered a way of introducing the 5' chain on the cyclopentane ring, compounds of more complicated structure were designed. The carbocyclic analogs of sinefungin with the amino group replaced by a hydroxyl substituent and a shortened 5'-C side chain became target compounds III and IV. Compound III was successfully synthesized as an epimeric mixture at the 9' carbon and results of its antiviral testing are forthcoming. Compound IV was difficult to make due to instability of intermediate aldehyde resulting in undesired mixture of stereoisomers at the 4' carbon. Furanosyl derivatives of sinefungin with side chain modifications were also designed as target compounds V and VI. Research toward those analogues provided an entry to a variety of carbocyclic nucleoside derivatives with a C-5' modified side chain.