Nucleic acids. 16. Orally active derivatives of ara-cytidine

Abstract

Water-soluble derivatives of ara-cytidine (cytarabine, Cytosar) were prepared and tested for antitumor, immunosuppressive, and antiarthritic activities in animals after oral administration. The compounds tested included the 5'-palmitate, 5'-benzoate, and 5'-adamantoate esters of ara-cytidine, made water soluble by use of their hydrochloride salts of peptidyl derivatives, and two basic 5' esters (5'-nicotinoate and 5'-quinuclidinate) as their hydrochloride salts. Five of the compounds had antitumor activity superior to that found with ara-cytidine itself after oral administration in the L1210 leukemic mouse assay. One of these, 5'-adamantoyl-ara-cytidine hydrochloride, had antitumor activity after oral administration approaching that achieved with parenterally administered ara-cytidine.

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…219 Drugs working through the former mechanism are Aciclovir (Zovirax) and Ganciclovir ( 110 , Scheme 14). Following a prodrug approach and earlier findings on adamantane-modified nucleobase derivatives, 9,220,221 Ganciclovir has been modified for topical application through esterification with lipophilic carboxylic acids, the prototype of which being adamantane-1-carboxylic acid. 222 When compared to 110 and the bis-propionate 111 , the bis-adamantanoylated prodrug 112 in addition to higher lipophilicity (see ALOGPs data in Scheme 14) also showed a markedly increased stability under acidic conditions, facilitating formulation and storage.…”

Chemoenzymatic Syntheses and Anti-HIV-1 Activity of Glucose−Nucleoside Conjugates as Prodrugs

“…Ara -cytidine is yet another drug that is poorly soluble in water, and prodrug approaches have been utilized to improve the oral bioavailability , . We believe that the synthesis of a glucose conjugate 10i would offer increased solubility for 20 in water.…”

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

“…Cytosine arabinoside triphosphate, the active form, damages the DNA of rapidly dividing cells and inhibits DNA and RNA polymerases and nucleotide reductase enzymes important for DNA synthesis. The drug has a limited activity against solid tumors due to the inactivation by cytidine deaminase, exonuclease degradation of the monophosphate form as well as the low retention and rapid elimination of the active triphosphate form (26)(27)(28). AraC lipid conjugates include N 4 -acyl derivatives, 5′-esters, and phospholipid conjugates (Fig.…”