Synthesis,In Vitro Anticancer Evaluation,and Interference with Cell Cycle Progression of N‐Phosphoamino Acid Esters of Zidovudine and Stavudine

A series of N‐diisopropylphosphoryl (DIPP) l‐amino acid ester prodrugs of zidovudine (AZT) (3a–3e) and stavudine (d4T) (4a–4e) has been prepared. The activity of these compounds against MCF‐7 cells (human pleural effusion breast adenocarcinoma cell line) and K562 cells (human chronic myeloid leukemia (CML) cell line) was evaluated. In difference from that of AZT amino acid phosphoramidates, the alophatic amino acid esters of AZT were found to be more cytotoxic than the aromatic analogues toward MCF‐7 cell. Two DIPP‐l‐amino acid esters of d4T 4b (CC₅₀ = 83 µM) and 4c (CC₅₀ = 182 µM) were found to be more cytotoxic than the parent drug toward K562 cells. MCF‐7 and K562 cell cycle disturbance was investigated showing detectable blockade in the S phase when exposed to biologically active AZT, 3a, 3b, 3c, 4b and 4c, indicating that they inhibit cell growth by blocking cell cycle progression. Together with previous reports, present findings suggest that anti‐breast cancer activity of AZT may be due to hamper DNA synthesis.     

3′-Azido-3′-deoxy-5′-O-isonicotinoylthymidine: A Novel Antiretroviral Analog of Zidovudine. II. Stability in Aqueous Media and Experimental and Theoretical Ionization Constants

Abstract

Degradation of 3′-azido-3′-deoxy-5′-O-isonicotinoylthymidine (AZT-Iso), an antiretroviral derivative of zidovudine, was investigated in buffer pH 7.4, µ = 300 mOsm at 37, 50 and 60°C, and in water (pH 6.6, 37°C), giving zidovudine (AZT) and isonicotinic acid (INA) as products. The rate constants were determined by reversed-phase HPLC showing pseudo-first-order kinetics related to the residual amount of AZT-Iso. In this way, the studied compound was demonstrated to be 153 times more stable in water than in buffer solution at 37°C. The analytical method was conveniently validated demonstrating to be a rapid and accurate stability-indicating technique. In addition, experimental and theoretical values of pKa were determined.