Marı́a J Comin

New progresses in the enantioselective synthesis and biological properties of carbocyclic nucleosides.

The recent advances in the chemistry of carbocyclic nucleosides focused on different synthetic approaches that lead to optically pure products as well as a comprehensive overview of their biological properties are discussed. In the latter aspect, molecular recognition of enzymes of pharmacological importance such as: reverse transcriptase, adenosine deaminase, thymidine kinase, DNA cytosine-C5 methyl transferase, S-adenosylhomocysteine hydrolase, etc are considered. The role of conformation and puckering of the glycon moiety in modulating the biological activity and also the use of carbanucleosides as building blocks to prepare oligonucleotides are carefully illustrated.

Evaluation of the antiviral activity of natural sulfated polyhydroxysteroids and their synthetic derivatives and analogs

Disodium 3beta,21-dihydroxypregn-5-en-20-one disulfate (2), sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3), sodium 3beta,21-dihydroxypregn-5-en-20-one 21-sulfate (4), and disodium 3beta,6alpha-dihydroxy-5alpha-pregnan-20-one disulfate (6) have been synthesized and completely characterized for the first time from readily available materials. Sulfation was performed using triethylamine-sulfur trioxide complex in dimethylformamide as the sulfating agent. Selective sulfation of 3beta,21-dihydroxypregn-5-en-20-one rendered sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3) as the major compound. The synthetic sulfated steroids as well as natural disulfated polyhydroxysteroids (7-9) isolated by us from the antarctic ophiuroid Astrotoma agassizii and the synthetic derivatives disodium 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene 3-acetate, 2,21-disulfate (7a) and 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene (7b) were comparatively evaluated for their inhibitory effect on the replication of one DNA (HSV-2) and two RNA (PV-3, JV) viruses. In general, steroids with sulfate groups at C-21 and C-2 or C-3 were the most effective in their inhibitory action against HSV-2 and also proved to be active against PV-3 and JV.

First Synthesis of (−)-Neplanocin C

Abstract (−)-Neplanocin C ( 4 ), a minor component of the neplanocin family of antibiotics and a lead drug for the design of several conformationally constrained nucleosides analogues, was enantioselectively synthesized starting from d -ribono-1,4-lactone via a convergent approach in twelve steps. The proton NMR spectrum of 4 was in agreement with the corresponding natural product. Calculated coupling constants obtained from ab initio molecular modeling studies and from previously published X-ray structure of neplanocin C also corresponded to the spectroscopic data.

Enantioselective synthesis of (+)-neplanocin F

Abstract (+)-Neplanocin F ((+ )-5 ), a minor component of the neplanocin family of antibiotics was enantioselectively synthesized starting from d -ribono-1,4-lactone via a convergent approach in 14 steps. This synthetic approach employed a regioselective protection of a secondary allylic hydroxyl group over a homoallylic one as key step.

Synthesis of conformationally locked carbocyclic nucleosides built on an oxabicyclo[3.1.0]hexane system

Abstract The rigid 6-oxobicyclo[3.1.0]hexane scaffold, characteristic of the natural antibiotic neplanocin C ( 3 ), was used to build prototypes of conformationally locked deoxynucleosides in the North hemisphere of the pseudorotational cycle. The purine analogues 6 and 7 are conformationally equivalent to carbocyclic nucleosides built with the bicyclo[3.1.0]hexane template. The pyrimidine nucleosides were unstable and underwent a facile intramolecular epoxide ring-opening reaction leading to heterocycle 22 . Only the deoxyguanosine analogue 7 showed antiviral activity against EBV.

Synthesis of c-5′-nor-Dideoxycarbanucleosides Structurally Related to Neplanocin C

Purine carbanucleosides built on a 6-oxabicyclo[3.1.0]hexane template were synthesized from readily available 2-cyclopentenone employing a Mitsunobu reaction to incorporate the base onto the carbocyclic ring. Both adenosine and guanosine analogues exhibited moderate antiviral activity.