Pamela Russ

Synthesis of Conformationally Restricted Carbocyclic Nucleosides: The Role of the O(4′)‐Atom in the Key Hydration Step of Adenosine Deaminase

Conformationally restricted carbocyclic nucleosides with either a northern(N)-type conformation, i.e., N-type 2′-deoxy-methanocarba-adenosine 8 ((N)MCdAdo), or a southern(S)-type conformation, i.e.S-type 2′-deoxy-methanocarba-adenosine 9, ((S)MCdAdo), were used as substrates for adenosine deaminase (ADA) to assess the enzymes preference for a fixed conformation relative to the flexible conformation represented by the carbocyclic nucleoside aristeromycin (10). Further comparison between the rates of deamination of these compounds with those of the two natural substrates adenosine (Ado; 1) and 2′-deoxyadenosine (dAdo; 2), as well as with that of the conformationally locked nucleoside LNA-Ado (11), which, like the natural substrates, has a furanose O(4′) atom, helped differentiate between the roles of the O(4′) anomeric effect and sugar conformation in controlling the rates of deamination by ADA. Differences in rates of deamination as large as 10000 can be attributed to the combined effect of the O(4′) atom and the enzymes preference for an N-type conformation. The hypothesis proposed is that ADAs preference for N-type substrates is not arbitrary; it is rather the direct consequence of the conformationally dependent O(4′) anomeric effect, which is more efficient in N-type conformers in promoting the formation of a covalent hydrate at the active site of the enzyme. The formation of a covalent hydrate at the active site of ADA precedes deamination. A new and efficient synthesis of the important carbobicyclic template 14a, a useful intermediate for the synthesis of (N)MCdAdo (8) and other conformationally restricted nucleosides, is also reported.

The Controlled Stereospecific Reduction of Cyclopentenyl Cytosine (CPE-C) to Carbodine and Isocarbodine

Abstract The preferential cis-addition of hydrogen to either face of the carbocyclic double bond of enantiomerically pure cyclopentenyl cytosine (1) was achieved. The resulting saturated carbocyclic nucleosides carbodine (2) and isocarbodine (3) were evaluated against human influenza virus. Carbodine showed the greater potency against this virus but the activity of isocarbodine was still substantial.

Conformational Analysis of Nucleosides Constructed on a Bicyclo[3.1.0]hexane Template. Structure-Antiviral Activity Analysis for the Northern and Southern Hemispheres of the Pseudorotational Cycle

Abstract A conformational analysis of carbocyclic nucleosides built on a rigid bicyclo[3.1.0]hexane template (1–4, Northern and 5–8 Southern) showed that the Northern conformation prefers an anti glycosyl torsion angle whereas the Southern conformation favors the syn range. Antiviral activity was mostly associated with the Northern conformers.

A new synthetic method for the synthesis of hydroxylated isoquinolines : preparation of methyl 6,7- and 7,8-dihydroxy-isoquinoline-3-carboxylates, potential protein-tyrosine kinase inhibitors

Synthesis of potential protein-tyrosine kinase inhibitors (6c) and (6e) is presented as a general procedure for the preparation of polyhydroxylated isoquinolines. Key features of the method include selective hydroxyl protection of tetrahydroisoquinolines by O-acylation followed by aromatization using MnO 2 . Quantitative deprotection of resulting O-acylisoquinolines is achieved using methanolic HCl

Synthesis and conformational analysis of locked carbocyclic analogues of 1,3-diazepinone riboside, a high-affinity cytidine deaminase inhibitor.

Cytidine deaminase (CDA) catalyzes the deamination of cytidine via a hydrated transition-state intermediate that results from the nucleophilic attack of zinc-bound water at the active site. Nucleoside analogues where the leaving NH3 group is replaced by a proton and prevent conversion of the transition state to product are very potent inhibitors of the enzyme. However, stable carbocyclic versions of these analogues are less effective as the role of the ribose in facilitating formation of hydrated species is abolished. The discovery that a 1,3-diazepinone riboside (4) operated as a tight-binding inhibitor of CDA independent of hydration provided the opportunity to study novel inhibitors built as conformationally locked, carbocyclic 1,3-diazepinone nucleosides to determine the enzyme’s conformational preference for a specific form of sugar pucker. This work describes the synthesis of two target bicyclo[3.1.0]hexane nucleosides, locked as north (5) and south (6) conformers, as well as a flexible analogue (7) built with a cyclopentane ring. The seven-membered 1,3-diazepinone ring in all the three targets was built from the corresponding benzoyl-protected carbocyclic bis-allyl ureas by ring-closing metathesis. The results demonstrate CDA’s binding preference for a south sugar pucker in agreement with the high-resolution crystal structures of other CDA inhibitors bound at the active site.

LESSONS FROM THE PSEUDOROTATIONAL CYCLE : CONFORMATIONALLY RIGID AZT CARBOCYCLIC NUCLEOSIDES AND THEIR INTERACTION WITH REVERSE TRANSCRIPTASE

Abstract Two conformationally locked carba-AZT nucleoside 5′-triphosphates built on a rigid bicyclo[3.1.0]hexane template showed exclusive Northern (2E) and Southern (3E) conformations, respectively. Inhibition of reverse transcriptase (RT) occurred selectively with the Northern carba-AZX triphosphate.

Hydroxyl- versus amide-directed cyclopropanation from the allylic position in 1-hydroxy-4-N-acyl-cyclopentenes under modified Simmons-Smith conditions

Abstract In a functionalized cyclopentene having allylic OH and NH-acyl groups on opposite faces of the ring, the diastereoselective delivery of the incoming methylene group in the diethylzinc version of the Simmons-Smith reaction was completely directed by the NH group. The diastereoselectivity of the reaction can be reversed by complete protection of the amide.

North- and south-bicyclo[3.1.0]hexene nucleosides: the effect of ring planarity on anti-HIV activity.

The syntheses of new conformationally locked North‐ and South‐bicyclo[3.1.0]hexene nucleosides is reported. The North analogues were synthesized by a convergent approach from the known (1S,2R,5R)‐5‐[(tert‐butyldiphenylsilyloxy)methyl]bicyclo[3.1.0]hex‐3‐en‐2‐ol by Mitsunobu coupling with the nucleobases. The South analogues were synthesized from their bicyclo[3.1.0]hexane nucleoside precursors by the selective protection of the primary hydroxy group, conversion of the secondary alcohol into a good leaving group, and base‐catalyzed elimination to generate the olefin. The transformation of a bicyclo[3.1.0]hexane nucleoside into a bicyclo[3.1.0]hexene nucleoside flattens the five‐membered ring of the bicyclic system and rescues anti‐HIV activity for North‐D4T, North‐D4A, and South‐D4C. The relationship between planarity and the anti/syn disposition of the nucleobase that is favored by a particular pseudosugar platform are proposed as key parameters in controlling biological activity.

Glycosylation of the active sequence ser-ile-lys-val-ala-val from the α1 chain of laminin reduces tumor cell attachment activity

Abstract N-terminal serine O-glycopeptides of SIKVAV-, a sequence located on the long arm of the α1 chain of laminin, were synthesized to study the effect of glycosylation on the adhesive properties of this biologically relevant peptide. The data show that covalently linked carbohydrates decrease the cell-attachment activity in a structurally dependent manner.