Susan Mary Daluge

An efficient, scalable synthesis of the HIV reverse transcriptase inhibitor Ziagen (1592U89).

Abstract Ziagen®, (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, was synthesized from (1S,4R)-azabicyclo[2.2.1]hept-5-en-3-one by efficient processes which bypass problematic steps in earlier routes. 2-Amino-4,6-dichloro-5-formamidopyrimidine is a key intermediate which makes possible an efficient construction of the purine from a chiral cyclopentenyl precursor.

Studies Designed to Increase the Stability and Antiviral Activity (HCMV) of the Active Benzimidazole Nucleoside, TCRB

The potent activity of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) against Human Cytomegalovirus with the concomitant low cellular toxicity at concentrations that inhibit viral growth prompted considerable interest in this research area. This interest was moderated by the pharmacokinetic studies of TCRB in rats and monkeys that revealed the instability of TCRB in vivo. These studies suggested that the instability was due to a cleavage of the glycosidic bond in vivo which released the heterocycle (2,5,6-trichlorobenzimidazole) into the bloodstream. This prompted us to initiate synthetic studies designed to increase the stability of the glycosidic bond of TCRB and BDCRB. Several synthetic approaches to address this and other problems are presented.

THE SYNTHESIS OF MODIFIED D- AND L-ANHYDROHEXITOL NUCLEOSIDES

Abstract The synthesis and antiviral activities of novel L-isomers 9–13 and modified D-guanine analogs 1d,e of recently reported anhydrohexitol nucleosides 1 are described. An efficient approach to known anhydrohexitol nucleoside precursor 2 from diacetone-D-glucose 3 is also reported.

Phosphoramidate protides of carbocyclic 2',3'-dideoxy-2',3'-didehydro-7-deazaadenosine with potent activity against HIV and HBV.

Synthesis of phosphoramidate protides of carbocyclic D‐ and L‐2′,3′‐dideoxy‐2′,3′‐didehydro‐7‐deazaadenosine by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t‐BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleosides against both HIV and HBV.

Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5′-triphosphate metabolite levels

The anti‐human immunodeficiency virus (HIV) activity of abacavir (ABC; 1‐(1S,4R)‐4‐[2‐amino‐6‐(cyclopropylamino)‐9H‐purin‐9‐yl]‐2‐cyclopentene‐1‐methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro‐ABC‐MP) to virus‐infected cell cultures. Metabolic studies with radiolabeled ABC and pro‐ABC‐MP in human T‐lymphocyte and primary macrophage cell cultures revealed a significantly increased delivery of the activated (phosphorylated) metabolite of ABC (ABC‐MP) by pro‐ABC‐MP, and the concomittant appearance of markedly higher intracellular levels of carbovir 5′‐triphosphate (CBV‐TP), which represents the eventual antivirally active metabolite of ABC. The intracellular amounts of ABC‐MP and appearance of CBV‐TP closely correlated with the extracellular pro‐ABC‐MP concentrations that were administered to the cell cultures within a concentration range between 0.5 and 100 μM. The highest amounts of CBV‐TP were observed within 6–24 h after drug administration. The improved delivery of ABC‐MP and metabolic conversion to CBV‐TP explain the markedly enhanced antiviral activity of the prodrug of ABC, and warrant further exploration of this prodrug technology on ABC and related compounds to further enhance and optimize their antiviral efficacy.

Phosphoramidate protides of 2',3'-dideoxy-3'-fluoroadenosine and related nucleosides with potent activity against HIV and HBV.

Abstract Syntheses of phosphoramidate protides of several 2′,3′-dideoxy-3′-fluoroadenosine derivatives by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleoside against HIV and HBV. Especially marked was the improvement in potency of phosphoramidate protides of 2′,3′-dideoxy-3′-fluoroadenosine against both HIV and HBV.

SYNTHESIS OF CARBOCYCLIC ANALOGS OF 2′,3′-DIDEOXYSANGIVAMYCIN, 2′,3′-DIDEOXYTOYOCAMYCIN, AND 2′,3′-DIDEOXYTRICIRIBINE

Syntheses and antiviral activity of new carbocyclic analogs of 2′, 3′-dideoxysangivamycin, 2′,3′-dideoxytoyocamycin and 2′,3′-dideoxytriciribine is described. The key intermediate, carbocyclic 4-chloro- 5-iodopyrrolopyrimidine, was synthesized in good yield via a novel iodination method using I2 and CF3COOAg. This carbocyclic 4-chloro-5-iodopyrrolopyrimidine then allowed for a concise synthesis of the desired 4,5-disubstituted carbocyclic nucleosides.

Synthesis of novel 8-substituted carbocyclic analogs of 2',3'-dideoxyadenosine with activity against hepatitis B virus.

ABSTRACT Synthesis and antiviral activity of several new 8-substituted carbocyclic analogs of D-2′,3′-dideoxyadenosine are described. The new 8-substituted analogs were synthesized via lithiation of carbocyclic 2′,3′-dideoxy adenosine followed by quenching with electrophiles. This methodology allows for a divergent synthesis of a variety of 8-substituted analogs from carbocyclic 2′,3′-dideoxyadenosine in high yields. 8-Methyl and 8-halogenated carbocyclic 2′,3′-dideoxyadenosine analogs showed 6–25 fold more activity against hepatitis B virus than the unsubstituted carbocyclic D-2′,3′-dideoxyadenosine.